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EJOP • Volume 5 • 2011/Issue 2 • €35
Editorial
Which role shall the pharmacists play in oncology
ECOP
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Guest Authors:
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Cover Story
Oral Chemotherapeutic Agents
Safe handling of oral chemotherapeutic agents:
a European perspective
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Editorial
For personal use only. Not to be reproduced without permission of the publisher ([email protected]).
Which role shall the pharmacists play in oncology
T
he European CanCer Organization (ECCO) describes itself as
‘the driving European force in
multidisciplinary and multiprofessional oncology’, and as existing ‘to uphold the right of all European cancer
patients to the best possible treatment and
care.’
Across Europe, cancer is now the second
highest cause of death overall, and the leading
cause of premature death before the age of 65
years in 28 of the 53 European countries [1].
There is therefore now a clear demand for
efficacious cancer therapies suitable for an
ageing population.
Klaus Meier
Editor-in-Chief
For the last 30 years, hazardous drugs, such as antineoplastic
chemotherapy agents, have commonly been used to treat
cancer patients. The potential risks of these compounds do
not only apply to the treated patients, but also to the pharmacists and other healthcare workers who need to handle them.
These risks include:
• adverse reproductive outcomes such as miscarriages, birth
defects, foetal losses, and infertility
• acute symptoms such as irritation, sore throat, cough, dizziness, headache, allergic reaction, diarrhoea, nausea, and
vomiting.
Because of these known safety issues, guidelines for the safe
handling of IV chemotherapy agents are now well established
in both hospitals and ambulatory oncology clinics.
In recent times, however, a few important environmental
changes have emerged. Firstly, the clinical and logistical
responsibilities for handling cytotoxic agents have fallen
increasingly on the pharmacist. Secondly, tumour therapy
documentation, quality management, and interdisciplinary
process standardisation have all gained importance. This has
culminated in expanded therapy protocols and more stringent
clinical treatment guidelines. Thirdly, as the number of oral
cancer treatments has increased, greater emphasis has been
placed on the prevention of non-adherence, errors of application, and interactions resulting from insufficient patient education.
As a result of these changes, adequate, quality-assured, multiprofessional care is now required for all oncology patients.
Pharmacists must collaborate with all other relevant members
of the healthcare team to ensure the delivery of the following
goals:
1. On-site optimisation of oral chemotherapy and improvement of pharmaceutical care
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
2. Provision of cost-effective and reliable
care through professional and timely
collaborations between local physicians,
pharmacists, and other healthcare professionals
3. Recognition and successful management
of chemotherapy-related issues
4. Enhancement of patient quality of life
through a coordinated management of
side effects and interactions during and
after therapy
5. Provision of a new insight which contributes to health service research and
encourages drug safety
Currently, quality control in the preparation
of cytotoxic drugs, and the exact role of the pharmacist with
regard to the handling and management of oral tumour therapies, is addressed in both European guidelines and directives,
and individual national/regional guidance. Oral tumour drug
handovers have traditionally been performed by trained hospital pharmacists, but in some countries, e.g. Germany, this
responsibility also extends to community pharmacists. This
poses a huge educational challenge, both in terms of teaching
pharmacists how to handle cytotoxic drugs safely, and in
explaining how best to communicate essential information to
patients.
In June 2011, the ESOP Secretary, Professor Per HartvigHonoré, spread the Society’s international ‘Pharmacist
Counselling Plan’ message at the Open Forum of the
European Partnership for Action Against Cancer (EPAAC) in
Madrid, Spain. This plan, which has been supported by seven
countries, clearly stipulates the future role that pharmacists
will play in this complex setting. I am sure that every one of
ESOP’s 2,500 members will be relishing the challenge!
Reference
1. Jakab Z. The cancer burden in the European Union and the European
Region: the current situation and a way forward. Presented at the
Informal Meeting of Health Ministers, Brussels, Belgium. 2010 Jul
4-5 [cited 2011 Jun 29]. Available from: www.euro.who.int/__
data/assets/pdf_file/0007/117088/RD_pres_cancer_burden.pdf
www.ejop.eu
3
Cover Story – Oral Chemotherapeutic Agents
For personal use only. Not to be reproduced without permission of the publisher ([email protected]).
Safe handling of oral chemotherapeutic agents:
a European perspective
Klaus Meier, PharmD; Niesha Griffith, MS; Susan Goodin, PharmD; et al.
In a series of roundtable meetings, a team of pharmacists from North America and Europe reviewed existing guidelines and identified
gaps in recommendations for handling of oral chemotherapeutic agents. The present article is a compilation of these gaps.
Introduction
Traditionally, chemotherapy has been administered by IV
infusion in an oncology inpatient unit or clinic or a physician’s
office. Over the past decade, however, self-administration of
oral chemotherapy has increased owing to the availability of
novel therapeutic agents [1-3]. In contrast to administration in
the institutional setting, where the prescribed medication, dose,
regimen, and response to therapy are subject to several levels of
assessment, patient or caregiver (defined as family members or
friends who assist the patient) administration of oral chemotherapy
is more likely to be susceptible to errors, non-adherence, and
increased adverse events as a result of a lack of coordinated care.
Accidental exposure to oral chemotherapy can occur at various
stages during the handling of these agents, i.e. transport, unpacking, storage, handling, administration, and disposal [4-6].
Thus, guidelines for safe and appropriate handling across the
healthcare continuum are imperative. Some of the existing
recommendations to ensure the safe handling of cytotoxic
oral chemotherapy are listed in Table 1 [2, 4, 7-24]. However,
the recommendations have not been universally accepted
or incorporated into practice. Recent surveys of healthcare
practitioners as well as patients found that the perception of oral
chemotherapy being safer than intravenous chemotherapy was
prevalent [25, 26]. In addition, a survey of pharmacy directors of
National Cancer Institute-designated cancer centres published
in 2007 identified gaps in pharmacy practices, safety assessments, and prescribing methods and demonstrated the need for
safe practice guidelines [27].
During a review of existing guidelines, our international panel of
pharmacists found that none of the guidelines addressed all areas
the panel deemed critical for the safe handling of oral chemotherapeutic agents. In our original article [28], we outlined recommendations to address these critical areas that could serve as
a starting point to build a framework for the safe storage, handling, administration, and disposal of oral chemotherapeutic
agents for manufacturers and distributors, healthcare workers,
and patients or their caregivers. Here within, these guidelines
are reproduced with the addition of commentary that points
out recommendations of particular importance to oncology
practitioners in many European countries.
Methods
Details of the methods used to develop these recommendations
are reported in our earlier article [28]. Briefly, an expert panel
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European Journal of Oncology Pharmacy • Volume 5 • 2011/2
comprising pharmacists from Austria, Canada, France, Germany,
Spain, UK, and the US, representing hospital, community,
ambulatory care, and specialty pharmacy convened for a series
of three roundtable meetings. Before the meetings, representatives from each country provided any current available national
recommendations for handling oral chemotherapy, including
guideline documents and institutional or country policies. In
addition, a literature review was performed through PubMed
Table 1: Guidelines and policies for safe handling of oral
chemotherapeutic agents
The US Department of Labor Occupational Safety and
Health Administration technical manual [7]
Guidelines from the American Society of Health-System
Pharmacists [12]
National Comprehensive Cancer Network (NCCN) Task
Force Report on Oral Chemotherapy [2]
Recommendations from the National Institute for Occupational Safety and Health (NIOSH) [8]
American Society of Clinical Oncology/Oncology Nursing
Society Chemotherapy Administration Safety Standards [19]
Association paritaire pour la santé et la sécurité du travail du
secteur affaires sociales (ASSTSAS) document (Canada) [4]
Guidelines from the Canadian Association of Pharmacy in
Oncology [16]
The European Society of Oncology Pharmacy (ESOP)
declaration [38]
National patient safety agency. Risks of incorrect dosing of
oral anti-cancer medications. NPSA/2008/RRR001 [20]
The Merseyside & Cheshire Cancer Network guidance
document (UK) [11]
The Society of Hospital Pharmacist of Australia Committee of
Specialty Practice in Cancer Services. Standards of Practice
for the Provision of Pharmaceutical Care of Patients Receiving
Oral Chemotherapy for the Treatment of Cancer [22]
Guidelines for the Safe Prescribing, Dispensing and
Administration of Cancer Chemotherapy; a consultative
report prepared by Clinical Oncological Society of
Australia, November 2008 [17]
The Grampians Integrated Cancer Service guidelines
(Australia) [9]
The Management and Awareness of Risks of Cytotoxic
Handling (MARCH) guidelines [24]
Relevant publications [10, 13-15, 18, 19, 21, 23]
www.ejop.eu
EJOP
to search for relevant publiFigure 1: Methodology involved
in the development of cations and existing guidethe recommendations lines through January 2010.
All the guidelines reviewed
for safe handling
at the meetings are listed in
Table 1. In addition to existing guidelines, the panel
also drew on best practices
that were based on the professional experience of its
members. A flow chart of
the methodology is shown
in Figure 1. The goal was
to develop a framework of
recommendations that can
be included in guidelines
specific to individual institutions and practices.
Recommendations for
safe handling
A number of stakeholders
are involved in handling oral
chemotherapeutic agents at
various stages. Recommendations for safe handling by
these stakeholders are outlined
in the following sections.
Manufacturers and
distributors
There are well defined regulations for manufacturers
and distributors to ensure
safe transport and handling
of chemotherapy drugs.
Although the initial step for
safe handling of oral chemotherapy agents begins with
the manufacturer, recommendations for manufacturers and distributors are not
included in current published
safe handling guidelines,
see Table 1, but the panel believes they play a pivotal role. Appropriate packaging could minimise the handling of chemotherapy by
healthcare providers and patients, contributing to safer handling.
This includes clear labelling on the outside of the package indicating that agent is cytotoxic. In addition, manufacturers should package only the amount of tablets or capsules needed for one cycle
of therapy. Because new regimens are constantly developed and
approved, another approach for manufacturers is to use unit-ofuse packaging, thereby reducing the need for packaging based on
a cycle of therapy. Each of these steps will ensure limited handling
of these agents. Finally, manufacturers are encouraged to develop
a liquid formulation or provide information on compounding a
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
liquid formation of their product for use by children or in special
circumstances such as patients with oral problems. Additional
recommendations for manufacturers and distributors are listed in
Table 2. Healthcare professionals are encouraged to reinforce the
importance of these points to stakeholders and regulatory agencies
whenever possible.
Healthcare providers
Healthcare providers have a major responsibility in ensuring
safe handling of oral chemotherapeutic agents. Because of the
significance of this responsibility, healthcare providers should be
appropriately trained, ensure that their knowledge is current with
developments in the field, and follow all applicable disciplinespecific guidelines when handling oral chemotherapeutic agents.
Training and competencies
As recommended in most safe handling guidelines, healthcare professionals should attend multiprofessional orientation
Table 2: Recommendations for manufacturers and distributors
Packaging and segregation
Effective packaging and segregation techniques should be
used to avoid contamination prior to distribution
Packaging should clearly state whether segregation techniques
have been used so that individuals unpacking the medications
can take additional precautions if necessary
Packaging material should be durable, able to contain any
accidental leakage during handling and transport, and tamperproof
Package label should indicate that the agent is cytotoxic, e.g.
size-appropriate modifications of the European Society of
Oncology Pharmacy yellow hand, the Association paritaire
pour la santé et la sécurité du travail du secteur affaires sociales
‘C’ symbol
Distributors should ensure that the labelling on the packaging is
intact and that oral cytotoxic agents are stored and transported
separately from non-cytotoxic agents
Minimising handling of oral chemotherapeutic agents
Manufacturers should provide the appropriate number of tablets
or capsules per packing based on the amount needed for one
cycle of therapy. If this approach is not an option, manufacturers
should attempt to use unit packaging, i.e. individual packaging
for tablets or capsules. Additionally, based on treatment
protocols for various diseases being treated and new data,
manufacturers should consider preparing additional dosage
strengths as appropriate
Because many patients inherently, or as a result of their
disease, have difficulty swallowing tablets or capsules, a liquid
formulation, or information on how to compound a liquid
formulation, should be provided by the manufacturer
Educational materials
Manufacturers should provide educational materials regarding
safe handling to each stakeholder, including physicians, registered nurses, pharmacy personnel, patients, and caregivers
Manufacturers should update patient education materials as
new information becomes available
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5
Cover Story – Oral Chemotherapeutic Agents
programmes and routine training courses specific to their roles.
They should also complete competencies associated with these
training programmes, along with an accompanying assessment for licensing qualification if applicable. The training
programmes should be approved by an oncology organisation
or appropriate local organisations [29, 30]. In addition, within a
healthcare institution, a primary educator should be established
as a source of referral and continued education for training
healthcare professionals on oral chemotherapy. This would
ensure that patients receive consistent education, training, and
monitoring across the multidisciplinary team [31, 32].
decontamination agent for use in the healthcare setting and the
patient’s home.
Healthcare workers should be trained and competent to treat
individuals accidently exposed to chemotherapeutic agents and
on the disposal of cytotoxic medications. All clinical staff who
are likely to come in contact with oral chemotherapeutic agents
or with waste from patients who have received these agents,
e.g. clerks, hygiene workers, and sanitation workers should
undergo appropriate training. The latter point of training nonhealthcare professional staff was important to the panel because
this recommendation is not included in any guidelines. With
the changing paradigm of oral chemotherapy, these individuals
should be appropriately trained as the traditional systems of
handling chemotherapy, and those involved, are more diverse
with oral chemotherapy. A list of training recommendations for
healthcare providers is compiled in Table 3.
Patient consent for oral chemotherapy should be obtained.
Patients should be consulted and assessed for their ability to
take oral therapy and to comply with their treatment plan. Tools
are available to assist with this evaluation [35]. Patients should
also be advised on all matters related to safe handling.
Storage and handling
Healthcare providers less than 18 years of age should not
handle oral chemotherapeutic agents. When handling oral
chemotherapeutic agents, healthcare providers must adhere
to good practice as defined by local standard operating
procedures and national guidelines. Key recommendations
are outlined in Table 3. In many countries in Europe, oral
chemotherapeutic agents are often available in unit packaging,
reducing the need for handling by the pharmacist. Therefore,
the recommendations regarding the handling of chemotherapeutic agents are applicable to those agents not available in
unit packaging or when additional manipulation of the dosage
form is required.
Handling of oral chemotherapy by pregnant staff initiated a
broad discussion by the panel, and no consensus was reached
regarding a recommendation. However, based on a 1992
directive of the Council of the European Communities, laws in
a majority of European countries mandate that pregnant women
should not work with cytotoxic agents [33].
Another issue for handling that generated a significant
discussion was the cleaning of non-disposable surfaces
exposed to chemotherapy drugs. Currently, there are limited
options for cleaning of these surfaces, although, in some
European countries, limited data support the use of cleaning
agents that have been validated for the removal of cytotoxic
agents [34]. The panel agreed further research is urgently
needed to develop a valid, readily available, and affordable
6
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
Patient counselling
Healthcare professionals should provide patients and caregivers
with education and training to ensure their understanding of
safe handling procedures as well as thorough knowledge of
proper administration of all medications. Patient literature and
other educational materials should be monitored and evaluated to ensure that current and accurate information is being
delivered.
All current medications should be reviewed with the patient
or caregiver to identify potential medication interactions
or interference with dietary requirements, and clear dosing
instructions should be provided, including what to do when a
dose is skipped or when vomiting of a dose (spillage) occurs.
During renewal of prescriptions, any potential medication
and food interactions must be reassessed and discussed with
the patient or caregiver. The patient should be made aware
of the required monitoring arrangements by being provided
with access to the written protocol and treatment plan from
the institution where the treatment was initiated. Patients who
are pregnant or breastfeeding should be counselled on recommended medications and their risk–benefit profiles.
Patients and caregivers
Recommendations for patients and caregivers are included in
some guidelines but are limited in details, so the panel focused
on these responsibilities and created a summary of dos and
don’ts for patients that could be put into practice and provided
to all patients, see Table 4. Caregivers should understand all
information given to patients, including the transport, storage,
dispensing, and disposal requirements to ensure safe handling.
They must work with the patient and healthcare providers
to ensure appropriate dosing for patients in their care and
report any treatment-related adverse effects. Caregivers who
are pregnant, breast-feeding, or children should not handle
any chemotherapy medications or waste products. Finally, to
further ensure the safety of these individuals and others in the
patient’s home, guidelines from Australia and Canada as well
as European Society of Oncology Pharmacy recommend one
or more of the following: handle patient’s clothes and bed linen
with gloves and wash separately from other items; double flush
the toilet after use, during treatment and four to seven days after
discontinuing chemotherapy; and clean toilet surfaces after use
by the patient [4, 9, 36]. These recommendations are supported
by a recent publication involving cyclophosphamide exposure
that showed significant contamination on and around the toilet
and that the use of gloves reduced personal contamination from
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EJOP
Table 3: Recommendations for healthcare providers
Table 3: (Continued )
Storage
Proper storage and handling of oral chemotherapeutic agents
should be ensured by healthcare professionals in order to
prevent accidental exposure and to ensure the integrity of
these medications
In healthcare institutions and pharmacies, cytotoxic agents
should be stored in a designated area per the manufacturer’s
instructions, and separate from non-cytotoxic agents.
Some agents are air-, moisture-, and/or light-sensitive;
therefore, storage specifications should be followed
Handling
Correct use of personal protective clothing and equipment
should be instituted to minimise exposure and health risks
[5, 6, 12]
Oral chemotherapeutic agents should not be dispensed
using automatic counting machines
Disposable gloves should be used for dispensing. Hands
must be washed before and after glove application
Manipulations such as compounding, crushing, cutting, or
splitting should be performed in a biological safety cabinet or
isolators* and should involve the use of personal protective
equipment, which should be disposable
Separate equipment should be used for cytotoxic and noncytotoxic agents
The pharmacist (or other qualified professional) should attempt
to limit additional handling of hazardous medications
by other healthcare professionals and should provide oral
chemotherapeutic agents in a ready-to-administer formulation†
Healthcare professionals who store and dispense oral chemotherapeutic agents must have a written emergency plan in the
event of a spill or accidental exposure. It is recommended that
annual spill simulation exercises be conducted
An updated list of hazardous medications should be readily
accessible to all healthcare personnel involved in handling of oral
chemotherapeutic agents
Disposal and cleaning of contaminated materials
All disposable protective clothing as well as any disposable
materials used while handling oral chemotherapeutic agents
should be disposed of as cytotoxic waste according to the
local waste disposal regulatory guidelines
All non-disposable materials exposed to chemotherapeutic
agents, including counting trays, tools, surfaces, etc. should be
washed or decontaminated‡ thoroughly after use
Training and competencies for safe handling
Healthcare professionals should attend orientation programmes
and routine training courses specific to their roles, and
should complete competencies associated with these training
programmes along with an accompanying assessment for
licensing qualification if applicable [29, 30]
A primary educator within a healthcare institution should be
established as a source of referral and continued education
on oral chemotherapy for healthcare professionals, allowing
for consistent education, training, and monitoring across the
multidisciplinary team [31, 32]
Healthcare workers involved in the handling of oral chemotherapy should be trained and competent to treat individuals
accidently exposed to chemotherapeutic agents and on the
disposal of cytotoxic medications
(Continued)
All clinical staff who are likely to come in contact with oral
chemotherapeutic agents or with waste from patients who
have received these agents, e.g. clerks, hygiene workers, and
sanitation workers should undergo appropriate training
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
*Because of the widespread use of isolators in many European
countries, the table in the original article [28] has been updated with
this information.
†
As oral syringes are rarely prepared from powder forms of medications
in European countries, the table in the original article [28] has been
modified to reflect this practice.
‡
In some European countries, limited data support the use of cleaning
agents that are validated for the removal of cytotoxic agents [34].
changing bed linens from one- to six-fold [37]. Because drugs
may be eliminated from the body as active or inactive metabolites in sweat, saliva, urine, or stool for five to seven half-lives,
the panel agreed these recommendations were important and
should be implemented.
Conclusion
In this article, we report on gaps in existing guidelines for the
safe handling of oral chemotherapeutic agents and highlight any
differences in North American and European perspectives. It is
encouraging to note that, for the most part, there is considerable
overlap in the standards for ensuring the safety of healthcare
professionals and patients with regard to the handling of oral
chemotherapeutic agents. The differences identified by us
include the overwhelming use of unit packaging and regulations
barring pregnant women from handling oral chemotherapeutic
agents in a majority of European countries.
Although the limitations of our approach include informal
methods of panel selection, the lack of a voting method for
consensus agreement, and a non-systematic literature review,
there are significant strengths to the recommendations. Firstly,
our recommendations are relevant to multiple stakeholders,
beginning with the manufacturer. In addition, although the
panel was comprised solely of pharmacists, this group has
significant experience with safe handling of hazardous agents
coupled with managing oral agents for all disease types.
On the basis of on our international experience and best
practices, we compiled key recommendations to fill the gaps of
existing guidelines. Therefore, this article, which provides an
international perspective, is timely, and is ideally suited to be
a framework for the development of safe handling guidelines
specific to individual institutions and practices.
Acknowledgement
Medical writing assistance was provided by Dr Meenakshi
P Subramanian and Dr Susan Sutch, Evidence Scientific Solutions, which was supported by Merck and Co, Inc.
This manuscript is an adaptation of the following article
published in the Journal of Oncology Practice: Goodin S
et al. Safe handling of oral chemotherapeutic agents in clinical
practice: recommendations from an international pharmacy
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7
Cover Story – Oral Chemotherapeutic Agents
Table 4: Specific recommendations for patients and their caregivers [39-42]
Dos for oral chemotherapy
Don’ts for oral chemotherapy
On receiving your prescription, review the package label, specifically Leave medication in open areas, near sources of water,
checking medication name and dosage [18]
direct sunlight, or where they can be accessed by
children or pets
Ensure that you completely understand when and how to take the Store medications in the areas where food or drinks
medication and ask questions if there is any confusion
are stored or consumed
Transport and store medicine as instructed and as outlined in the packaging Crush, break, or chew tablets
label [18]
Use gloves if possible and wash hands thoroughly before and after glove Double up on doses, unless instructed by a healthcare
application*
professional
If gloves are not worn, tip tablets and capsules from their container/
blister pack directly into a disposable medicine cup
Administer the medication as instructed
Share prescriptions or medication
Keep a journal of adverse effects. Make a list of adverse effects for Assume that oral chemotherapy is safer than IV
whichever healthcare professional has to be contacted immediately
chemotherapy
Consider using adherence devices. Use separate devices for cytotoxic Skip doses unless instructed by your physician
and non-cytotoxic agents
Report any overdosing immediately
Discard medication down the toilet or in the garbage
Keep information ready for necessary action in the event of accidental
exposure (including emesis and accidental ingestion) [14, 18]
Return wet, damaged, unused, discontinued, or expired medications to
the pharmacist or hospital for disposal [18]
Report all medications (prescription and non-prescription as well as
complementary and alternative medicines) and any specific dietary
requirements to the healthcare provider/prescriber at the time of
assessment and consultation. Inform other healthcare professionals that
you are on oral chemotherapy, e.g. surgeons and dentists
Minimise the number of individuals coming in contact with the cytotoxic
medications [18]
Wash the patient’s clothes and bed linen separately from other items*
[4, 9]
Double flush the toilet after use during, and four to seven days after
discontinuing oral chemotherapy [4, 9]
*It is recommended that caregivers wear gloves at all times while handling oral chemotherapeutic agents as well as contaminated items in order to
minimise risk of exposure.
panel. J Oncol Pract. 2011 Jan;7(1):7-12. Reprinted with
permission. ©2011 American Society of Clinical Oncology.
All rights reserved.
Karen Chuk, BScPhm
Outpatient Pharmacy Site Operations, University Health
Network – Princess Margaret Hospital, Toronto, Ontario
Canada
Author for correspondence
Klaus Meier, PharmD
Department for Clinical and Hospital Pharmacy
Heidekreis-Klinikum GmbH
30 Oeninger Weg
DE-29614 Soltau, Germany
Mikael Daouphars, PharmD, PhD
Cancer Centre Henri Becquerel, Rouen, France
Christian Doreau, PharmD
Consultant Hospital Pharmacist, CD Conseil
Antibes, France
Co-authors
Niesha Griffith, MS
Department of Pharmacy, Arthur G James Cancer Hospital
Ohio State University, Columbus, Ohio, USA
Beth Chen, PharmD
Biologics Inc, Cary, North Carolina, USA
8
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
Rinku A Patel, PharmD
Diplomat Specialty Pharmacy, Deerfield, Illinois, USA
Rowena Schwartz, PharmD
Weinberg and Oncology Pharmacy, Johns Hopkins Hospital
Baltimore, Maryland, USA
www.ejop.eu
EJOP
María José Tamés
Hospital Pharmacist Specialist
Pharmacy Department, Onkologikoa, San Sebastian, Spain
Robert Terkola, aHPh
Pharmacy Department, Sozialmedizinisches Zentrum Süd
Kaiser-Franz-Josef-Spital mit Gottried von Preyer’schem
Kinderspital, Vienna, Austria
Barbara Vadnais, MSc
University of Montreal, Faculty of Pharmacy, Montreal
Quebec, Canada and Maisonneuve-Rosemont Hospital
Montreal, Quebec, Canada
Debbie Wright, DPharm
Southampton Oncology Centre, Southampton General
Hospital, Southampton, UK
Susan Goodin, PharmD
Division of Pharmaceutical Sciences, Cancer Institute
of New Jersey, Robert Wood Johnson Medical School,
New Brunswick, New Jersey, USA
References
1. Aisner J. Overview of the changing paradigm in cancer treatment: oral
chemotherapy. Am J Health Syst Pharm. 2007;64(9 Suppl 5):S4-S7.
2. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report:
Oral chemotherapy. J Natl Compr Canc Netw. 2008;6(Suppl 3):
S1-S14.
3. Greco FA. Evolving role of oral chemotherapy for the treatment of
patients with neoplasms. Oncology (Williston Park). 1998;12(3 Suppl 4):
43-50.
4. AASTSAS (Association paritaire pour la santé et la sécurité du travail
du secteur affaires sociales). Prevention guide: safe handling of
hazardous drugs. [cited 2010 September 28]. Available from: www.
irsst.qc.ca/files/documents/PubIRSST/CG-002.pdf
5. Sessink PJ, Bos RP. Drugs hazardous to healthcare workers. Evaluation
of methods for monitoring occupational exposure to cytostatic drugs.
Drug Saf. 1999;20(4):347-59.
6. Valanis B, Vollmer W, Labuhn K, Glass A. Occupational exposure to
antineoplastic agents and self-reported infertility among nurses and
pharmacists. J Occup Environ Med. 1997;39(6):574-80.
7. US Department of Labor – Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs.
In: OSHA Technical Manual. Washington, DC: US Department of
Labor – Occupational Safety and Health Administration; 2008: Section
VI: Chapter 2.
8. National Institute for Occupational Safety and Health (NIOSH).
Preventing occupational exposure to antineoplastic and other hazardous drugs in health care setting. 2004; Centers for Disease Control
and Prevention NIOSH Publication No. 2004-165.
9. Grampians Integrated Cancer Service (GICS) Grampians Regional
Palliative Care Team. Clinical guidelines for the administration
of oral chemotherapy agents in the community setting. [cited 2011
January 24]. Available from: www.gics.com.au/resources/ClinGuidelinesForOralChemoInCommunity.pdf
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
10. Gallagher TH, Lucas MH. Patients’ and physicians’ attitudes regarding
disclosure of harmful medical errors. In: ASCO 2005 Educational
Book. Alexandria, VA: American Society of Clinical Oncology; 2005:
254-58.
11. Merseyside & Cheshire Cancer Network. Network guidance for safe
prescribing, handling and administration of cytotoxic drugs. [cited 2011
January 24]. Available from: www.mccn.nhs.uk/userfiles/documents/
MCCN%20Safe%20Prescribing%20handling%20%20administration%20of%20Cytotoxic%20Drugs_April06_revDec07_
oral%20 August%2008_vincOct08.pdf
12. American Society of Health-Systems Pharmacists. ASHP guidelines
on handling hazardous drugs. [cited 2010 May 10]. Available from:
www.ashp.org/s_ashp/docs/files/BP07/Prep_Gdl_HazDrugs.pdf
13. Barbería E, Hernandez C, Miralles V, Maroto M. Paediatric patients
receiving oncology therapy: review of the literature and oral
management guidelines. Eur J Paediatr Dent. 2008;9(4):188-94.
14. Birner A. Safe administration of oral chemotherapy. Clin J Oncol
Nurs. 2003;7(2):158-62.
15. Birner AM, Bedell MK, Avery JT, Ernstoff MS. Program to support
safe administration of oral chemotherapy. J Oncol Pract. 2006;2(1):
5-6.
16. Canadian Association of Pharmacy in Oncology (CAPhO). Standards
of practice for oncology pharmacy in Canada, version 2. [cited 2010
May 10]. Available from: www.capho.org/docs/StandardsofPractice/
StandardsofPracticeFORWEBV2Dprintable.pdf
17. Clinical Oncological Society of Australia (COSA). Guidelines for
the safe prescribing, dispensing and administration of cancer chemotherapy. [cited 2011 January 24]. Available from: www.cosa.org.au/
cosa_assets/files/About%20us%20-%20publications/Guidelines%20
for%20Safe%20Prescribing2008.pdf
18. Griffin E. Safety considerations and safe handling of oral chemotherapy agents. Clin J Oncol Nurs. 2003;7(Suppl 6):25-9.
19. Jacobson JO, Polovich M, McNiff KK, et al. American Society of
Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards. J Clin Oncol. 2009;27(32):5469-75.
20. National Patient Safety Agency. Oral anti-cancer medicines: risks of
incorrect dosing – Rapid Response Alert. [cited 2011 January 24].
Available from: www.nrls.npsa.nhs.uk/resources/?entryid45 = 59880
21. Pratt S. The Oncology Roundtable: oral anticancer agents: implications
for patient management and program economics. The Advisory Board
Company. Practice Brief #31. Washington, DC; 2002.
22. Society of Hospital Pharmacists of Australia (SHPA) Committee of
Specialty Practice in Cancer Services. SHPA Standards of practice
for the provision of oral chemotherapy for the treatment of cancer J
Pharm Pract Res. 2007;37(2):149-52.
23. Viele CS. Managing oral chemotherapy: the healthcare practitioner’s
role. Am J Health Syst Pharm. 2007;64(9 Suppl 5):S25-S32.
24. Management and Awareness of Risks of Cytotoxic Handling
(MARCH) guidelines. Safe handling of oral chemotherapy. [cited
2011 January 24]. Available from: marchguidelines.com/members/
guidelines/PNF1_OralChemotherapy.aspx
25. Johnson PE, Chambers CR, Vaida AJ. Oncology medication safety: a
3D status report 2008. J Oncol Pharm Pract. 2008;14(4):169-80.
26. Chan A, Leow YC, Sim MH. Patients’ perspectives and safe handling
of oral anticancer drugs at an Asian cancer center. J Oncol Pharm Pract.
2009;15(3):161-5.
www.ejop.eu
9
Cover Story – Oral Chemotherapeutic Agents
27. Weingart SN, Flug J, Brouillard D, et al. Oral chemotherapy safety
practices at US cancer centres: questionnaire survey. Brit Med J.
2007;334(7590):407.
28. Goodin S, Griffith N, Chen B, et al. Safe handling of oral chemotherapeutic agents in clinical practice: recommendations from an international pharmacy panel. J Oncol Pract. 2011;7(1):17-21.
29. Goodin S, ed. Advancing the safe and appropriate use of oral chemotherapy agents. Am J Health Syst Pharm. 2007;64(Suppl 5):36-40.
30. Birner A, Rezendes M. Oral chemotherapy. Clin J Oncol Nurs.
2005;9(1):107-9.
31. Blecher C, Barefoot J, Davis D, et al. A team approach toward promoting patient adherence to oral chemotherapy protocols. Abstract
2985. Oncol Nurs Forum. 2008;35(3):537.
32. Hartigan K. Patient education: the cornerstone of successful oral
chemotherapy treatment. Clin J Oncol Nurs. 2003;7(6 Suppl):21-4.
33. EUROPA Council of European Communities. Council Directive 92/85/
EEC of 19 October 1992 on the introduction of measures to encourage
improvements in the safety and health at work of pregnant workers
and workers who have recently given birth or are breastfeeding. [cited
2011 January 24]. Available from: eur-lex.europa.eu/smartapi/cgi/
sga_doc?smartapi!celexplus!prod!DocNumber&lg = en&type_doc =
Directive&an_doc = 1992&nu_doc = 85
34. Kiffmeyer TK, Niemöller M, Schirpenbach R, et al. External
contamination of drug packaging. Suggestions for a cleaning
procedure. Krankenhauspharmazie. 2001;22(5):207-12.
35. Elliott RA, Marriott JL. Standardised assessment of patients’ capacity
to manage medications: a systematic review of published instruments.
BMC Geriatr. 2009;9:27.
36. German Society of Oncology Pharmacy. QuapoS 4: quality standard
for the oncology pharmacy service with commentary. European
Society of Oncology Pharmacy Conference for Standardisation in
Oncology Pharmacy and the continuing Workshop at the 6th EU
NZW-Conference in Hamburg. Luxumbourg and Hamburg, 2008
September and 2009 January. [cited 2011 January 24]. Available
from: www.esop.li/downloads/library/quapos4_english.pdf
37. Fransman W, Vermeulen R, Kromhout H. Dermal exposure to cyclophosphamide in hospitals during preparation, nursing and cleaning
activities. Int Arch Occup Environ Health. 2005;78(5):403-12.
38. European Society of Oncology Pharmacy (ESOP). ESOP declarations:
oral antineoplastic therapy basic considerations. [cited January 28,
2011]. Available from: www.esop.li/downloads/oral_antineoplastic_
therapy.pdf
39. Singh BN, Malhotra BK. Effects of food on the clinical pharmacokinetics of anticancer agents: underlying mechanisms and implications for oral chemotherapy. Clin Pharmacokinet. 2004;43(15):
1127-56.
40. Goodin S. Oral chemotherapeutic agents: understanding mechanisms
of action and drug interactions. Am J Health Syst Pharm. 2007;
64(9 Suppl 5):S15-S24.
41. Bartel SB. Safe practices and financial considerations in using
oral chemotherapeutic agents. Am J Health Syst Pharm. 2007;64
(9 Suppl 5):S8-S14.
42. Wong CM, Ko Y, Chan A. Clinically significant drug–drug
interactions between oral anticancer agents and nonanticancer agents:
profiling and comparison of two drug compendia. Ann Pharmacother.
2008;42(12):1737-48.
Oncology Pharmacy Practice
For personal use only. Not to be reproduced without permission of the publisher ([email protected]).
Implementing quality in the preparation of
cytotoxic drugs
The pharmacy department must ensure that the treatment the patient receives is safe, effective and timely. This
can be achieved by maintaining quality standards.
Introduction
final check of finished products, completed prescriptions and their release.
In order to preserve and enhance the ability of
the pharmacy staff to meet the needs of the
cancer patient, all quality standards must be
agreed and set. These standards must also be
constantly monitored and documented in order
to be maintained. This short article summarises
the key points that must be put in place to implement a quality system in the hospital pharmacy.
Quality manual and policy
Jeff Koundakjian
BPharm, MRPharmS
Acomplete quality manual must be accessible and
a quality policy must be in place. A mission statement should also
be prepared with a document stating the objectives of the facility.
Personnel
The pharmacy should have a documented organisational structure
that clearly indicates the responsibilities and accountability of each
member of staff. A register should be held of the people qualified
to prescribe, dispense, release and collect the completed preparation. Each member of staff must have a regular evaluation and a
tailored training programme relevant to their job description and
an individual training record.
Staff records should be kept of individual personnel workload
together with exposure to cytotoxic agents. Accidents and injuries
at work should be recorded, as should any absences from work due
to illness.
Further required SOPs include worksheet preparation and check; assembly and check of raw materials
and disposables; any transfer, labels and labelling,
use of protective clothing; entering and leaving the
clean room; the packaging and storage of finished
products; delivery of the finished products; handling spillage and waste; the ordering, receipt, storage and shelf-life of starting materials; formulary
and protocol compilation and clinical trials.
Records must be made for all adverse incidents and near misses,
investigations and actions taken and of all complaints received,
regardless of the source. A regular summary report of these should
also be produced, including the investigations and actions taken.
Audits
Audits, both internal and external, must be undertaken on a regular basis to monitor implementation and compliance with the
agreed standards. There should be a named, independent quality
assurance person for both types of audit.
Capacity planning
Observations made during the audits should be recorded, together
with any recommendations for corrective measures, which must be
reviewed at the next audit or, if serious, as soon as possible. The audit
report should be submitted to the Director of Pharmacy and a
timescale agreed to remedy any deficiencies. The final report should
be submitted to the Chief Executive of the hospital or clinic.
There must be a document stating the current capacity and available
measures for handling changes in workload. Arrangements must be
in place for emergency dispensing and a detailed contingency plan
must be available to cover any unforeseen suspension of service.
This article is based on a presentation by the author at the 7th
Symposium of the International Society of Oncology Pharmacy
Practitioners (ISOPP) 2010 in Prague, Czech Republic.
Documentation and standard operating procedures
Author
An approved, comprehensive documentation system must be prepared and all documents must be clear, detailed and reviewed regularly at defined intervals. Standard Operating Procedures (SOPs)
are required for LAFC/isolator usage, cleaning, decontamination,
facilities, and equipment. Records must be retained for the original
construction specifications and validation documents of equipment
and facilities, and also for the operation, cleaning, maintenance
and fault logs.
Jeff Koundakjian, BPharm, MRPharmS
Lead Pharmacist
North Wales Cancer Network
BOPA Executive Committee Member
Preswylfa, Hendy Road
Mold CH7 1PZ, UK
SOPs are also required for generic substitutions; additions and
changes to the prescription form and its approval; prescription
check and verification including any alteration; approval for the
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
Further reading
Quality Standard for the Oncology Pharmacy Service with
Commentary (QuapoS 4), January 2009.
Beaney AM, editor. Quality Assurance of Aseptic Preparation
Services 4th ed. London: Pharmaceutical Press; 2006.
www.ejop.eu
11
Scientific Review
For personal use only. Not to be reproduced without permission of the publisher ([email protected]).
Systematic reviews of resection of metastases
in metastatic colorectal cancer
Meredith Edwards, BMedSci, MBBS; Zhongyun Zhao, PhD; Shkun Chadda, BSc, MSc; Beth Barber, PhD
Abstract
Study objectives: Three systematic literature reviews in metastatic colorectal cancer (mCRC) were performed, one to assess
initial resectability rates, one to assess resection rates after conversion therapy for initially unresectable metastases, and one to
assess survival following post-conversion therapy resection. Conversion therapy consists of mainly systemic therapies that are
used to shrink tumours sufficiently to allow resection in previously unresectable disease.
Materials and methods: Relevant articles were identified through three separate electronic searches of MEDLINE, MEDLINE
In-Process, the Excerpta Medica Database (EMBASE) and the Cochrane Library, and through manual searches of the reference
lists of identified articles. The MEDLINE and EMBASE searches were limited to articles published in English, whereas the
Cochrane Library search had no language restrictions.
Results: Sixteen studies examined initial resectability, and reported definitions of resectability and resection rates. Resection
rates varied greatly, ranging from 4–55%. Seventy-four clinical studies investigated resection after conversion therapy for initially
unresectable metastases (liver, lung or mixed). Again, they reported a wide variation in resection rates, with overall resection
rates ranging from 1–75% and complete resection rates (R0) from 0–39%. From the 29 studies reporting post-conversion
therapy resection survival data, overall median survival ranged from 20–63 months and median progression-free survival from
13 to 20 months.
Conclusion: The findings from these systematic literature reviews suggest that mCRC resection data from different studies should
be interpreted and compared with caution due to differences between studies in definitions of resectability, study designs, patient
populations, the year when studies were conducted, and the country/centre where patients were treated.
There is a need for more data on conversion therapy, particularly using monoclonal antibodies, and for long-term survival postconversion therapy resection. Pharmacy practice is encouraged to initiate or participate in retrospective or prospective research
which examines conversion therapy in their institution.
Keywords: Conversion therapy, metastatic colorectal cancer, monoclonal antibodies, resection rates, survival, systematic review
Introduction
Colorectal cancer (CRC) is currently the third most common
cancer worldwide [1]. Approximately 20–25% of patients with
the disease already have metastases at the time of diagnosis [2],
and about 50–60% of patients diagnosed with the disease will
eventually develop metastases [3, 4]. The most common sites
of metastases in metastatic CRC (mCRC) are the liver and
the lung [5]. For most patients with mCRC, treatment is palliative rather than curative. The goals of systemic treatment in
these patients are to prolong survival and to maintain quality of
life for as long as possible [6].
However, 10–20% of patients with mCRC have metastases
that are resectable, and may potentially be cured through surgical resection of the metastases [7]. An additional 15–20% of
patients whose metastases are not initially resectable may be
converted to a potentially curable state by additional therapy
(mainly systemic therapy), known as ‘conversion therapy’, followed by surgical resection of the metastases [8]. Thus, the
goal of conversion therapy is to shrink, i.e. downstage, the
metastases so that surgical resection can be performed [6].
The current standard systemic therapies for mCRC are chemotherapies and the monoclonal antibodies (mAbs) bevacizumab, cetuximab and panitumumab. The most commonly used
chemotherapy backbones are FOLFOX (leucovorin, 5FU and
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European Journal of Oncology Pharmacy • Volume 5 • 2011/2
oxaliplatin) and FOLFIRI (leucovorin, 5FU and irinotecan).
Bevacizumab, a mAb against vascular endothelial growth factor
A (VEGF-A), was first approved as a treatment for mCRC in
2004, followed by cetuximab (also in 2004) and panitumumab
(2006). Cetuximab and panitumumab both target the epidermal
growth factor receptor (EGFR) and are effective only in wildtype KRAS mCRC. Panitumumab is the only approved fully
human anti-EGFR monoclonal antibody, while cetuximab is
a chimeric agent. Recent studies suggest that the addition of
mAbs to chemotherapy regimens offers benefits in mCRC
in terms of increased response rates and increased resection
rates [9-17].
The objective of this study was to systematically review the
literature to assess initial resection rates, and resection rates
and survival post-conversion therapy in patients with mCRC.
This systematic review was performed principally to understand the existing data to facilitate hypothesis generation for
further work.
Materials and methods
Search strategy
Three separate electronic searches were performed, one to
evaluate rates of initial resectability, i.e. no conversion therapy
required; one to evaluate resection rates after conversion therapy for initially unresectable metastases; and one to evaluate
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EJOP
survival following post-conversion therapy resection. The
databases searched were MEDLINE, MEDLINE In Process,
the Excerpta Medica Database (EMBASE) and the Cochrane
Library. In addition to the electronic searches, manual searching
of reference lists was performed. Citations/abstracts of identified studies were reviewed and assessed for relevance by two
independent analysts. Full paper copies of studies considered
to be relevant were then reassessed for inclusion against the criteria outlined below. Disagreements between the two analysts
were resolved by discussion until a consensus was reached.
For each search, data from relevant publications were extracted
into a data extraction table by one analyst according to a predefined set of parameters. The data table was then checked for
accuracy and detail by a second independent analyst.
be reported as part of the study inclusion process or as patient
characteristics.
Inclusion and exclusion criteria
Inclusion criteria were: studies estimating the percentage of
mCRC patients with initially resectable metastases (liver or
lung); studies evaluating the proportion of mCRC patients with
initially unresectable liver or lung metastases who were eligible
for resection following conversion therapy; or studies evaluating
the survival of mCRC patients after resection of liver or lung
metastases following conversion therapy. For completeness of
the systematic reviews, conversion therapy included not only
systemic therapy but also hepatic arterial infusion (HAI) or
mixed HAI/systemic therapy. The systemic therapies of interest were the mAbs bevacizumab, cetuximab and panitumumab
(alone or in combination with chemotherapy) and the standard chemotherapy regimens FOLFOX, FOLFIRI and XELOX
(oxaliplatin and the oral drug capecitabine).
Data were also analysed according to the method of conversion
therapy: systemic (including chemotherapy and mAb therapy),
HAI, or mixed HAI/systemic therapy; and according to whether
conversion therapy contained a mAb agent. The conversion rate
was defined as the percentage of patients converted from having initially unresectable metastases to having resectable metastases. The resection rate after conversion therapy was defined
as the proportion of patients who actually underwent attempted
curative resection of metastases following conversion therapy.
Relevant studies were required to be observational, randomised
or non-randomised, single or multicentre, retrospective or
prospective, and phase II, III or IV in design. Meta-analyses,
systematic reviews, case series, registries, and abstracts from
meetings of the American Society of Clinical Oncology
and the European Society for Medical Oncology were also
included.
Results
Exclusion criteria were: studies of non-metastatic CRC; studies
of the prevention or detection of CRC; studies of potential
biomarkers in patient samples; in vitro, preclinical or phase I
studies; and editorials, letters to the editor, case reports, commentaries, interview-based research, legal cases, newspaper
articles or patient education leaflets.
The MEDLINE and EMBASE searches were limited to articles published in the English language, whereas the Cochrane
Library search had no language restrictions. None of the
searches were limited by date.
The aim of these systematic reviews was to be exhaustive.
Thus, studies reporting relevant data for each review were
included provided they did not fulfil any of the exclusion criteria. Included studies were not required to report relevant data
as a primary or secondary endpoint, meaning that data could
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
Definitions
In this study, data on conversion and resection rates, and survival after post-conversion resection, were grouped according
to the location of the downstaged metastases: liver, lung or
mixed. Liver metastases were further subdivided as selected
(metastases confined to the liver only) or non-selected (liver and
extra-hepatic metastases). The mixed group included studies
where the location of downstaged metastases was either not
specified or mixed, i.e. the patient population included patients
with liver only metastases, liver and extrahepatic metastases,
and/or lung metastases only.
Data analysis
Extracted data from relevant studies were summarised into a
macro-enabled Excel spreadsheet (one for each search). No
statistical tests were performed; thus, all findings are presented
descriptively.
Initial resectability
A total of 792 citations/abstracts were identified in the search for
data on initially resectable metastases. Of these, 61 underwent fullpaper review. After analysis of the full papers, 13 relevant studies
remained. In addition, three studies were identified from manual
searching, giving a total of 16 relevant studies. Of these, 15 reported
data on initially resectable CRC liver metastases, see Table 1. These
studies were published between 1978 and 2009. No systematic
reviews or randomised, controlled trials (RCTs) were identified;
all studies were either observational or a case series.
Proportion of patients with initially resectable metastases
and resection rates
Two types of relevant data were identified in the literature:
(1) data on the proportion of patients with metastases considered
resectable (regardless of whether resection was then actually
performed); and (2) data on the proportion of patients who
actually underwent resection of metastases without receiving any
conversion therapy. Ten out of 15 studies presented data on the
proportion of patients with liver metastases that were considered
initially resectable: this proportion ranged from 9.3–55%. All
15 studies reported data on the proportion of patients who actually
underwent resection of metastases without receiving any conversion treatment: this proportion ranged from 4–55%, see Table 1.
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Scientific Review
Table 1: Resection rates for initially resectable liver metastases (no conversion therapy)
References
Definition of resectability
Definition of
unresectability
Number
of patients
with liver
metastases
Number
of patients
with initially
resectable liver
metastases
(% of all liver
metastases)
Number of
patients who
underwent
resection
of initially
resectable liver
metastases
(% of all liver
metastases)
Wanebo et al.
1978 [18]
NS
NS
217
NS
29 (13%)
Bismuth et al.
1996 [19]
No predefined criteria of
resectability with regard
to number or size of
tumours, or to locoregional
invasion of perihepatic
structures, provided
resection was complete and
macroscopically curative
Large size, ill location,
multinodularity, and
extrahepatic disease
434
104 (24%)
104 (24%)
Isenberg et al.
1996 [20]
No extrahepatic progression,
in good general condition,
1–4 liver metastases
involving ⬍ 40% of liver
parenchyma
NS
142
NS
17 (12%)
Harms et al.
1999 [21]
Complete resection of the
primary cancer, absence of
extrahepatic tumours, and
technical ability to resect
liver metastases completely
Tumour growth, number
or distribution of
metastases, and/or poor
performance status
449
245 (55%)
245 (55%)
230
94 (41%)
84 (37%)
Wigmore et al. No evidence of extrahepatic
NS
1999 [22]
dissemination, and metastases
able to be safely resected
with reasonable probability of
clearing macroscopic disease
Lambert et al.
2000 [23]
ⱕ 4 metastases in a
distribution believed to be
resectable with intent to cure
Extrahepatic disease
318
73 (23%)
49 (15%)
Rosen et al.
2000 [24]
NS
NS
96
NS
34 (35%)
Adam et al.
2001 [25]
NS
Large size, ill location,
multinodularity, and
extrahepatic disease
872
171 (20%)
171 (20%)
Heslin et al.
2001 [26]
Patients who are technically
NS
resectable and physically able
to undergo the operation
174
NS
52 (30%)
Moore et al.
2002 [27]
ⱕ 4 hepatic metastases,
disease confined to one
lobe of the liver and no
extrahepatic disease
NS
194
52 (27%)
23 (12%)
Adam et al.
2004 [28]
NS
Not possible to perform
a curative hepatectomy
leaving at least 30%
of nontumoural liver
parenchyma, or the
presence of concomitant
extrahepatic disease
1439
335 (23%)
335 (23%)
(Continued )
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European Journal of Oncology Pharmacy • Volume 5 • 2011/2
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EJOP
Table 1: Resection rates for initially resectable liver metastases (no conversion therapy) (Continued )
References
Definition of resectability
Definition of
unresectability
Number
of patients
with liver
metastases
Number
of patients
with initially
resectable liver
metastases
(% of all liver
metastases)
Sjovali et al.
2004 [29]
Patients ⬍ 80 years old
without indications of
extrahepatic disease,
surviving ⬎ 30 days
after diagnosis of hepatic
metastases, ⬍ 5 hepatic
metastases
NS
NS
537
50 (9%)*
Number of
patients who
underwent
resection
of initially
resectable liver
metastases
(% of all liver
metastases)
21 (4%)
NS
37
NS
9 (24%)
NS
Predicted residual
45
functional liver remnant
⬍ 35% after 1 cm margin
of resection, patient
physically unfit for
operation, evidence of
extrahepatic disease not
amenable to resection,
more than liver-only
metastasis (metastases to
liver and other organs)
NS
669
20 (44%)
17 (38%)
312 (47%)
253 (38%)
Titu et al.
2006 [30]
Cheng et al.
2008 [31]
Xu et al.
2009 [32]
Liver metastasis focus ⱕ 4 or
liver metastasis focus ⬎ 4 but
localised to semi-liver lobe,
the remnant liver volume
ⱖ 30%, without other organ
metastasis or peritoneum
polar lymph node metastasis
*Hypothetical number as all liver metastases patients potentially resectable according to imposed criteria; NS: not specified.
Only two studies reported data on the resection of initially
resectable CRC lung metastases [24, 33]. Brister et al. [33]
reported that 9% of patients had initially resectable lung metastases, and 8% of patients underwent actual resection of these
metastases. Rosen et al. [24] reported that six patients (55% of
included patients with lung metastases) underwent resection
of lung metastases with no use of conversion therapy.
Definitions of resectability/unresectability
Of the 15 studies reporting relevant initial resectability data for
liver metastases, 10 (67%) gave a definition of resectability. These
definitions varied greatly between studies, see Table 1. Authors
included the following criteria in these definitions: absence of
extrahepatic tumours (6 studies); technical ability to resect the
metastases (5 studies); ⱕ 4 liver metastases (4 studies); patient
in good general condition/physically able to undergo the operation (2 studies); complete resection of the primary cancer
(1 study); metastases involving ⬍ 40% of the liver parenchyma
(1 study); disease confined to one lobe of the liver (1 study);
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
patients ⬍ 80 years of age and surviving ⬎ 30 days after the
diagnosis of metastases (1 study); and ⬎ 4 liver metastases but
localised to the semi-liver lobe and the remnant liver volume
ⱖ 30% (1 study).
In six studies (40%), a definition of unresectability of liver metastases was given, see Table 1. Criteria included in these definitions
were: extrahepatic disease (6 studies); large size, ill location
and multinodularity (3 studies); patient unfit for operation/poor
performance status (2 studies); not possible to perform curative hepatectomy leaving at least 30% of non-tumoural liver
parenchyma (1 study); and predicted residual functional liver
remnant < 35% after resection (1 study).
No studies provided a definition of resectability for lung
metastases, but one study [33] gave a definition of unresectability:
disseminated malignancy, multiple lung metastases, recurrence
at primary site, unresectable primary tumour, associated disease,
or terminal state.
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15
Scientific Review
Conversion and resection of initially unresectable
metastases
A total of 789 citations/abstracts were identified in the search
for data on conversion therapy and resection rates after conversion therapy for initially unresectable metastases. Of these,
154 underwent full-paper review. After analysis of the full
papers, 41 relevant studies remained. In addition, 34 studies
were identified from manual searching, giving a total of 75
relevant studies. Of these, one was a systematic review and 16
were RCTs.
The included systematic review [34] evaluated irinotecan,
oxaliplatin and raltitrexed in the treatment of advanced
CRC. In this review, a total of 11 studies were identified that
included conversion therapy data. Resection rates following conversion therapy ranged from 9–35% for irinotecan-based
combination therapy and from 7–51% for oxaliplatin-based
combination therapy.
Data on conversion rates and resection rates from the 74
clinical studies are summarised in Table 2. Not every study
Table 2: Summary of conversion and resection rates for initially unresectable metastases from 74 clinical studies with
relevant data
Location of Type of
metastases conversion
therapy
Liver,
(selected)
HAI
Systemic
Mixed HAI/
systemic
Liver (non- HAI
selected)
Systemic
Mixed
Lung
Mixed HAI/
systemic
HAI
Systemic
Mixed HAI/
systemic
All
Conversion therapy Number
subgroup
of relevant
studies and
date range
NA
9 studies1
(1999–2009)
Chemotherapy and/ 19 studies2
or biologic therapy
(1999–2010)
Including
1 study3 (2009)
bevacizumab
Including cetuximab 2 studies4
(2008, 2010)
Including
No data found
panitumumab
NA
6 studies5
(2002–2009)
NA
No data found
Chemotherapy and/ 21 studies6
or biologic therapy
(1996–2009)
Including
1 study7 (2009)
bevacizumab
Including cetuximab 5 studies8
(2007–2009)
Including
No data found
panitumumab
NA
2 studies9
(2007, 2009)
NA
No data found
Chemotherapy and/ 23 studies10
or biologic therapy
(2000–2010)
Including
2 studies11
bevacizumab
(2008, 2010)
Including cetuximab 3 studies12
(2007–2009)
Including
No data found
panitumumab
NA
No data found
NA
No data found
Conversion
rates
23–61%
Resection rates
after conversion
therapy (all
resection)
4–47%
Resection rates
after conversion
therapy (complete
resection, R0)
3–36%
10–44%
10–75%
8–41%
No data found
15%
12%
No data found
75%*
30–38%
No data found
No data found
No data found
No data found
10–57%
16–39%
No data found
6.5–43%
No data found
2–48%
No data found
2–30%
No data found
8%
6%
7%
7–30%
5–30%
No data found
No data found
No data found
No data found
5%
0–21%
No data found
17%
No data found
1–32%
No data found
2–25%
No data found
8–9%
No data found
No data found
23–27%
5–21%
No data found
No data found
No data found
No data found
No data found
No data found
No data found
No data found
No data found
HAI: hepatic arterial infusion; NA: not applicable; *Only 15/20 patients evaluated.
1
[35–43], 2[15, 44–61], 3[15], 4[56, 59], 5[43, 62–66], 6[15, 16, 19, 25, 28, 67–82], 7[15], 8[16, 76–78, 80], 9[83, 84], 10[9, 13, 52, 54, 60, 80, 85–101],
11
[13, 101], 12[9, 80, 100].
16
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
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EJOP
reported the three outcomes of conversion rate, resection rate
and complete resection rate (R0). Among those that reported
conversion rates, the rates ranged from 6.5–61%; for those
reporting resection rates post-conversion therapy, the rates
ranged from 1–75%; among studies reporting the rate of complete resection (R0), the rate ranged from 0–41%, see Table 2.
No data on the use of conversion therapy for lung metastases
were found.
Survival following post-conversion therapy resection
A total of 1,589 citations/abstracts were identified in the electronic search. Of these, 566 were considered to be possibly
suitable for full-paper review. The 566 citations/abstracts
were reassessed to ensure that they included conversion therapy and survival data, leaving 98 articles for full-paper review.
After analysis of the full papers, 22 relevant studies remained.
In addition, eight studies were identified from manual searching, giving a total of 30 relevant studies. Of these, one was a
systematic review and three were RCTs.
The systematic review was identified in the search for
conversion rate and resection rate data for initially unresectable metastases, see above [34]. Of the 11 studies identified
in the systematic review by Hind et al. [34], only two studies
provided survival data on post-conversion therapy resection:
the 5-year overall survival (OS) rate was 5–26% and the 5-year
disease-free survival rate was 3–11% with oxaliplatin-based
combination therapy.
Twenty-nine of the 30 studies identified in the current
review reported survival data following post-conversion
therapy resection. These data are summarised in Table 3.
Not every study reported all four outcomes of interest:
OS, progression-free survival (PFS), 3-year survival rate,
and 5-year survival rate. The median OS ranged from 20 to
63 months and median PFS from 13 to 20 months among
studies reporting these outcomes. The 3-year survival rate
ranged from 50–86% in studies reporting 3-year survival
data and the 5-year survival rate ranged from 33–94% in
studies reporting this outcome measure. No data for survival following post-conversion therapy resection of lung
metastases were found, and only one study with survival
data following conversion therapy containing a mAb was
identified.
Discussion
In the current systematic review, resection rates for initially
resectable metastases varied greatly between studies from
4–55%, along with a wide variation in the definitions of
resectability between studies. Similarly, great variation was
also observed in post-conversion therapy resection rates (range
1–75%), and in the proportion of patients that achieved complete resection (range 0–39%). After post-conversion therapy
resection, overall median survival ranged from 20 to 63 months
and median PFS ranged from 13 to 20 months. The majority of
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
the studies that were identified focused on liver metastases, and
only very limited data for lung metastases were found.
There are several possible reasons for the large variation in
resection rates. First, as the results of this review showed, definitions of resectability/unresectability varied greatly between
studies, not just for initially resectable metastases but also for
post-conversion therapy resection. In some studies, definitions
of resectability/unresectability were unclear or absent. Even
today, resectability is still not well defined [108].
Second, surgeon opinion as to which liver metastases are resectable is evolving over time with advancing surgical techniques.
Until recently, the classic contraindications for resection of
mCRC liver metastases were four or more metastases, disease
outside the liver, metastatic nodes in the liver pedicule, a
resection margin of less than 1 cm, the presence of co-morbid
disease, incomplete resection of the primary tumour, and the
involvement of more than two sushepatic veins [108]. However,
advances in surgery and systemic therapy have improved the
feasibility of performing liver metastases resection, and these
contraindications are now outdated.
Third, none of the studies identified examined resection rates
as a primary or secondary endpoint. Thus, the data could be
affected by uncontrolled bias. Additionally, study patient populations varied between studies. Patient age, gender and comorbidities are factors that are likely to influence the decision about
whether or not to perform resection. In some studies, it was not
clear whether the patient population with liver metastases was
‘selected’ (metastases confined to the liver) or ‘unselected’
(liver and extrahepatic metastases).
Fourth, resectability and thus resection rates are likely to depend
on the centre where the patient is treated, as this can vary across
countries, regions, centres, and even oncology surgeons, partly
due to differing experience [48]. Finally, resection rates have
been increasing since the year 2000 due to improved surgical
interventions, and the introduction of new chemotherapeutic
and biological agents [109, 110]. Indeed, the evolution in systemic therapies has resulted in increased objective response rates
[108]. Thus, the year in which the study was conducted could
also have an influence on resectability and resection rates.
A large proportion of the studies reporting conversion therapy
data for initially unresectable liver metastases were retrieved by
manual searching (34/75; 45%). Possible reasons for the manual identification of such a large proportion of relevant articles
include the fact that the searching of electronic databases relies
on the correct indexing of articles and the use of appropriate
key words in the titles/abstracts of articles. Since resection
rates were not a study endpoint, it is likely that relevant studies
would not necessarily include appropriate search terms in the
title or abstract and would therefore be less easily identifiable
in an electronic database search.
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17
Scientific Review
Table 3: Survival following post-conversion therapy resection from 29 clinical studies with relevant data
Location of Type of
metastases conversion
therapy
Conversion
therapy
sub-group
Number
of relevant
studies and
date range
Liver
(selected)
HAI
NA
5 studies1
63
(2000–2009)
Systemic
Chemotherapy 9 studies2
39–60
and/or biologic (1999–2007)
therapy
Liver (nonselected)
Mixed
Overall
median
survival
(months)
Median PFS
(months)
3-year
survival
rate (%)
5-year
survival
rate (%)
No data found
56–86%
35–71%
14–17
67–73%
34–50%
Including
bevacizumab
None
No data found No data found
No data found
No data found
Including
cetuximab
None
No data found No data found
No data found
No data found
Including
panitumumab
None
No data found No data found
No data found
No data found
Mixed HAI/ NA
systemic
1 study3
(2003)
No data found 20
65%
No data found
HAI
None
No data found No data found
No data found
No data found
50–63%
33–40%
Systemic
NA
4
20–41
Chemotherapy 8 studies
and/or biologic (1996–2009)
therapy
13
Including
bevacizumab
None
No data found No data found
No data found
No data found
Including
cetuximab
1 study5
(2007)
20
No data found
No data found
Including
panitumumab
None
No data found No data found
No data found
No data found
Mixed HAI/ NA
systemic
2 studies6
No data found No data found
(2002, 2007)
No data found
39–94%
HAI
NA
None
No data found
No data found
Systemic
40–47
Chemotherapy 4 studies7
and/or biologic (2004–2006)
therapy
No data found
No data found
No data found
13
No data found No data found
Including
bevacizumab
None
No data found No data found
No data found
No data found
Including
cetuximab
None
No data found No data found
No data found
No data found
Including
panitumumab
None
No data found No data found
No data found
No data found
None
No data found No data found
No data found
No data found
Mixed HAI/ NA
systemic
HAI: hepatic arterial infusion; NA: not applicable; PFS: progression-free survival.
1
[36, 38, 39, 41, 42], 2[44, 45, 47, 48, 50, 51, 53, 102, 103], 3[63], 4[19, 25, 28, 67, 75, 77, 104, 105], 5[77], 6[106, 107], 7[90, 91, 93, 96].
The current review also found that survival following postconversion therapy resection has not been well studied. In particular, long-term (over 5 years) survival data were lacking.
This highlights the need for studies that could provide such
data; for example, prospective interventional trials, observational studies or registries.
18
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
Conclusion
In these systematic reviews resection rates in patients with
mCRC varied greatly between studies, mainly due to differences in the definitions of resectability, study designs, patient
populations, the year when studies were conducted, and the
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country/centre where patients were treated. As a consequence,
it was difficult to compare resection rates between studies and
between treatments identified in the literature.
There is a need for more data on conversion therapy, particularly
using monoclonal antibodies, and for long-term survival postconversion therapy resection. Pharmacy practice is encouraged
to initiate or participate in retrospective or prospective research
which examines conversion therapy in their institution.
Acknowledgement
This study was funded by Amgen Inc. Additional editorial support was provided by PRMA Consulting Ltd, UK.
Conflict of interest
Dr Meredith Edwards and Ms Shkun Chadda are employees of
PRMA Consulting and received research funding from Amgen
Inc. Dr Zhongyun Zhao and Dr Beth Barber are employees
and stockholders of Amgen Inc. Amgen Inc provides financial
support to the study but the authors are responsible for study
design, analysis and interpretation of data.
Author for correspondence
Meredith Edwards, BMedSci, MBBS
PRMA Consulting
Centaur House
Ancells Business Park
Ancells Road
Fleet, Hampshire GU51 2UJ, UK
Co-authors
Zhongyun Zhao, PhD
Shkun Chadda, BSc, MSc
Beth Barber, PhD
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(FA)/oxaliplatin (L-OHP) (CPT-FFL) in colorectal liver metastases.
ASCO Gastrointest Cancers Symp. 2008.
www.ejop.eu
EJOP
57. Ychou M, Viret F, Kramar A, et al. Tritherapy with fluorouracil/
leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II
study in colorectal cancer patients with non-resectable liver metastases. Cancer Chemother Pharmacol. 2008;62(2):195-201.
58. Skof E, Rebersek M, Hlebanja Z, Ocvirk J. Capecitabine plus
Irinotecan (XELIRI regimen) compared to 5-FU/LV plus Irinotecan
(FOLFIRI regimen) as neoadjuvant treatment for patients with unresectable liver-only metastases of metastatic colorectal cancer: a randomised prospective phase II trial. BMC Cancer. 2009;9:120.
59. Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response
and secondary resectability of colorectal liver metastases following
neoadjuvant chemotherapy with cetuximab: the CELIM randomised
phase 2 trial. Lancet Oncol. 2010;11(1):38-47.
60. Watkins DJ, Chau I, Cunningham D, et al. Defining patient outcomes
in stage IV colorectal cancer: A prospective study with baseline stratification according to disease resectability status. Br J Cancer. 2010;
102(2):255-61.
61. Zhao R, Zhu J, Ji X, et al. A phase II study of irinotecan and capecitabine for patients with unresectable liver-only metastases from colorectal cancer. Jpn J Clin Oncol. 2010;40(1):10-6.
62. Piedbois P. Intravenous CPT-11/5-FU/LV and hepatic artery infusion
pirarubicin in non operable liver metastases from colorectal cancer.
A study of the AERO Group. Ann Oncol. 2002;13:291P.
63. Zelek L, Bugat R, Cherqui D, et al. Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined
with hepatic arterial infusion pirarubicin in non-resectable hepatic
metastases from colorectal cancer (a European Association for
Research in Oncology Trial). Ann Oncol. 2003;14(10):1537-42.
64. Ducreux M, Ychou M, Laplanche A, et al. Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with
inoperable hepatic metastases: a trial of the Gastrointestinal Group of
the Federation Nationale des Centres de Lutte Contre le Cancer. J Clin
Oncol. 2005;23(22):4881-7.
65. Boige V, Malka D, Elias D, et al. Hepatic arterial infusion of oxaliplatin and intravenous LV5FU2 in unresectable liver metastases from
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66. Kemeny NE, Melendez FD, Capanu M, et al. Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for
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67. Rivoire M. De Cian F, Meeus P, et al. Combination of neoadjuvant
chemotherapy with cryotherapy and surgical resection for the treatment of unresectable liver metastases from colorectal carcinoma:
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68. Moehler M, Hoffmann T, Zanke C, et al. Safety and efficacy of outpatient treatment with CPT-11 plus bolus folinic acid/5-fluorouracil as
first-line chemotherapy for metastatic colorectal cancer. Anticancer
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69. Recchia F, Nuzzo A, Lalli A, et al. Multicenter phase II study of
CPT-11 fractionated over two days with bimonthly leucovorin and
5-fluorouracil in patients with metastatic colorectal cancer. Anticancer
Res. 2003;23(3C):2903-8.
70. Recchia F, Rea S, Nuzzo A, et al. Oxaliplatin fractionated over two
days with bimonthly leucovorin and 5-fluorouracil in metastatic colorectal cancer. Anticancer Res. 2004;24(3b):1935-40.
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71. Teufel A, Steinmann S, Siebler J, et al. Irinotecan plus folinic acid/
continuous 5-fluorouracil as simplified bimonthly FOLFIRI regimen for
first-line therapy of metastatic colorectal cancer. BMC Cancer. 2004;4:38.
72. Aparicio J, Fernandez-Martos C, Vincent JM, et al. FOLFOX alternated with FOLFIRI as first-line chemotherapy for metastatic colorectal cancer. Clin Colorectal Cancer. 2005;5(4):263-7.
73. Benoist S, Pautrat K, Mitry E, et al. Treatment strategy for patients
with colorectal cancer and synchronous irresectable liver metastases.
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74. Seium Y, Stupp R, Ruhstaller T, et al. Oxaliplatin combined with irinotecan and 5-fluorouracil/leucovorin (OCFL) in metastatic colorectal cancer: a phase I-II study. Ann Oncol. 2005;16(5):762-6.
75. Capussotti L, Muratore A, Mulas MM, et al. Neoadjuvant chemotherapy and resection for initially irresectable colorectal liver metastases.
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76. Folprecht G, Lutz MP, Schoffski P, et al. Cetuximab and irinotecan/5fluoroouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing
metastatic colorectal carcinoma. Ann Oncol. 2006;17(3):450-6.
77. Adam R, Aloia T, Levin F, et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to
conventional systemic therapy. J Clin Oncol. 2007;25:4593-602.
78. Min BS, Kim NK, Ahn JB, et al. Cetuximab in combination with
5-fluorouracil, leucovorin and irinotecan as a neoadjuvant chemotherapy in patients with initially unresectable colorectal liver metastases.
Onkologie. 2007;30(12):637-43.
79. Muratore A, Zorzi D, Bouzari H, et al. Asymptomatic colorectal cancer with un-resectable liver metastases: immediate colorectal resection or
up-front systemic chemotherapy? Ann Surg Oncol. 2007;14(2):766-70.
80. Tabernero J, Van Cutsem E, Diaz-Rubio E, et al. Phase II trial of
cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin
Oncol. 2007;25:5225-32.
81. Fuse N, Doi T, Ohtsu A, et al. Safety of irinotecan and infusional fluorouracil/leucovorin (FOLFIRI) in Japan: a retrospective review of 48 patients
with metastatic colorectal cancer. Int J Clin Oncol, 2008;13(2):144-9.
82. Vasile E, Masi G, Fornaro L, et al. A multicenter phase II study of
the combination of oxaliplatin, irinotecan and capecitabine in the
first-line treatment of metastatic colorectal cancer. Br J Cancer.
2009;100(11):1720-4.
83. Carnaghi C, Santoro A, Rimassa L, et al. The efficacy of hybrid
chemotherapy with intravenous oxaliplatin and folinic acid and intrahepatic infusion of 5-fluorouracil in patients with colorectal liver
metastases: A phase II study. Invest New Drugs. 2007;25(5):479-85.
84. Seki H, Ozaki T, Shiina M. Hepatic arterial infusion chemotherapy
using fluorouracil followed by systemic therapy using oxaliplatin plus
fluorouracil and leucovorin for patients with unresectable liver metastases from colorectal cancer. Cardiovasc Intervent Radiol. 2009;32(4):
679-86.
85. De Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil
with or without oxaliplatin as first-line treatment in advanced colorectal
cancer. J Clin Oncol. 2000;18:2938-47.
86. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter
randomized trial of oxaliplatin added to chrono-modulated fluorouracilleucovorin as first-line treatment of metastatic colorectal cancer. J Clin
Oncol. 2000;18:136-47.
www.ejop.eu
21
Scientific Review
87. Wein A, Riedel C, Köckerling F, et al. Impact of surgery on survival
in palliative patients with metastatic colorectal cancer after first line
treatment with weekly 24-hour infusion of high-dose 5-fluorouracil
and folinic acid. Ann Oncol. 2001;12(12):1721-7.
88. Masi G, Allegrini G, Cupini S, et al. First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/
leucovorin (FOLFOXIRI): results of a phase II study with a simplified
biweekly schedule. Ann Oncol. 2004;15(12):1766-72.
89. Sørbye H, Glimelius B, Berglund A, et al. Multicentre phase II study
of Nordic fluorouracil and folinic acid bolus schedule combined with
oxaliplatin as first-line treatment of metastatic colorectal cancer. J Clin
Oncol. 2004;22:31-8.
90. Tournigan C, Andre T, Achille E, et al. FOLFIRI followed by
FOLFOX6 or the reverse sequence in advanced colorectal cancer: a
randomized GERCOR study. J Clin Oncol. 2004;22(2):229-37.
91. Delaunoit T, Alberts SR, Sergent DJ, et al. Chemotherapy permits
resection of metastatic colorectal cancer: Experience from intergroup
N9741. Ann Oncol. 2005;16(3):425-9.
92. Kohne CH, Van Cutsem E, Wils J, et al. Phase III study of weekly
high-dose infusional fluorouracil plus folinic acid with or without
irinotecan in patients with metastatic colorectal cancer: European
Organisation for Research and Treatment of Cancer Gastrointestinal
Group Study 40986. J Clin Oncol. 2005;23(22):4856-65.
93. Quintela-Fandino M, Gravalos C, Gonzalez E, et al. Irinotecan (CPT-11)based chemotherapy as induction treatment for advanced colorectal
cancer. Anticancer Drugs. 2005;16(1):31-8.
94. Giacchetti S, Bjarnason G, Garufi C, et al. Phase III trial comparing
4-day chronomodulated therapy versus 2-day conventional delivery of
fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of
metastatic colorectal cancer: the European Organisation for Research
and Treatment of Cancer Chronotherapy Group. J Clin Oncol.
2006;24(22):3562-9.
95. Souglakos J, Androulakis N, Syrigos K, et al. FOLFOXIRI
(folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI
(folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in
metastatic colorectal cancer (MCC): a multicentre randomised phase
III trial from the Hellenic Oncology Research Group (HORG). Br J
Cancer. 2006;94:798-805.
96. Tournigan C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized
study of FOLFOX4 or FOLOX7 with oxaliplatin in a stop-and-go
fashion in advanced colorectal cancer - a GERCOR study. J Clin
Oncol. 2006;24(3):394-400.
97. Andre T, Tournigan C, Mineur L, et al. Phase II study of an optimized
5-fluorouracil-oxaliplatin strategy (OPTIMOX2) with celecoxib
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LV5FU2 or simplified LV5FU (HD-FOLFIRI) for patients with
untreated metastatic colorectal cancer: a new way to allow resection
of liver metastases? Oncology. 2008;74(1–2):17-24.
Chibaudel B, Maindrault-Goebel F, Lledo G, et al. Can chemotherapy
be discontinued in unresectable metastatic colorectal cancer? The
GERCOR OPTIMOX2 Study. J Clin Oncol. 2009;27(34):5727-33.
Raoul JL, Van Laethem JL, Peeters M, et al. Cetuximab in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) in the
initial treatment of metastatic colorectal cancer: a multicentre twopart phase I/II study. BMC Cancer. 2009;9:112.
Kopetz S, Hoff PM, Morris JS, et al. Phase II trial of infusional
fluorouracil, irinotecan, and bevacizumab for metastatic colorectal
cancer: efficacy and circulating angiogenic biomarkers associated
with therapeutic resistance. J Clin Oncol. 2010;28:453-9.
Barone C, Nuzzo G, Cassano A, et al. Final analysis of colorectal
cancer patients treated with irinotecan and 5-fluorouracil plus folinic
acid neoadjuvant chemotherapy for unresectable liver metastases.
Br J Cancer. 2007;97(8):1035-9.
Lau WY, Lai EC. Hepatic resection for colorectal liver metastases.
Singapore Med J. 2007;48(7):635-9.
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J Clin Oncol. 2009;27(11):1829-35.
Malik HZ, Farid S, Al Mukthar A, et al. A critical appraisal of the
role of neoadjuvant chemotherapy for colorectal liver metastases:
a case-controlled study. Ann Surg Oncol. 2007;14(12):3519-26.
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and improved chemotherapy. J Clin Oncol. 2009;27(22):3677-83.
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Feature – Pharmacoeconomics
For personal use only. Not to be reproduced without permission of the publisher ([email protected]).
An Italian model to evaluate appropriateness
and effectiveness of drugs
The national and regional registries of drugs in Italy provide effective models to appraise drugs newly
introduced to the market and determine reimbursement prices.
T
he requirement for every new drug
approval is the demonstration of
net clinical benefit, but even randomised controlled clinical trials
may fail to demonstrate relevance
in modifying the natural history of a disease,
and costs may be too high in relation to the benefits to the population that may be obtained.
(monitoraggio-farmaci.agenziafarmaco.it), as
an appraisal of new drugs introduced into the
Italian market.
The website has since been extended to drugs
of different categories, e.g. orphan drugs, antidiabetic, anti-HIV, antipsoriatic, cardiovascular
and ophthalmology drugs. Preliminary registration is required for the institution/departThe cost of bringing a new drug to the marment and the dispensing pharmacy, and then
Angelo C Palozzo
ket from discovery to phase III clinical trials is
the physician is allowed to prescribe from a list
PharmD
estimated at Euros 0.5–1.1 billion and requires
of high-cost oncology drugs. Every prescriber
8–10 years [1]. These high development costs
has to enter information on:
are translated into increasing costs to patients receiving the new
• the patient’s vital statistics, disease, drug schedule (first time)
drugs (or society as a whole when this is charged to national
• toxicity, variations in dosage, final outcome (follow-up).
health services). Recently, new models have been proposed to
accelerate the registration and the availability to the market of
If all the elements match the required parameters, the prea new drug [2].
scription is allowed and the hospital pharmacist can dispense
the drug. Standard reports are then made available on a local
The ‘accelerated model’ is more often implemented by the EMA
(hospital), regional and national basis. Table 1 shows the
or FDA for oncology drugs, but this fast-track authorisation
RFOM national statistics up to 28 September 2010.
requires post-marketing studies to verify both effectiveness
and lack of toxicity in the general population. Furthermore,
Furthermore, the AIFA has recently adopted methods to
the national health services need tools to determine the reimappraise innovation and determine the reimbursement price
bursement price for each drug. In the UK, the National Instiof new drugs. In a document approved in July 2007, an AIFA
tute for Health and Clinical Excellence (NICE) systematically
working group suggested the following algorithm to estabassesses drugs and health technologies, and usually suggests the
lish drug innovation [4]:
reimbursement of the proposed drug or technology to the UK
National Health Service. The NICE preferred method to assess
Figure 1: Risk sharing or pay by result or by performance
the value of an intervention is the quality-adjusted life year [3].
NHS total reimbursement
Efficacy evaluation
In December 2005, the Italian Medicines Agency (Agenzia
Italiana del Farmaco, AIFA) activated a web-based national
registry of oncology drugs, the Registro AIFA-onco or RFOM
RESPONDER
Treatment goes on
NON RESPONDERS
No. of treatment cycles
Table 1: RFOM national statistics up to 28 September
2010
No. of enabled hospitals
788
No. of enabled hospitals with at least one patient
registered
589
No. of enabled hospital departments
1,332
No. of enabled physicians
2,104
No. of enabled pharmacists
24
789
No. of registered patients
109,121
No. of patients eligible for treatment
103,085
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
(3)
Treatment ends
(1)
(2)
(1) Cost-sharing: 50% discount to NHS on ‘ex-factory’ price for the first
cycles of therapy, e.g. erlotinib, non-small cell lung cancer (NSCLC).
(2) Pay by result: 100% discount to NHS on ‘ex-factory’ price when
treatment ends after one, e.g. lapatinib, metastatic breast cancer, or
two, e.g. sorafenib, hepatocarcinoma, cycles.
(3) Combined methods: 50% discount to NHS on ‘ex-factory’price for
first cycles of therapy and ‘capping’on payment after seven months
of treatment, e.g. bevacizumab, colorectal, breast, NSCLC, renal
cancers.
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EJOP
1. Definition in severity of disease
a. treatment of severe disease
b. treatment of risk factors in severe disease
c. treatment of mild disease
2. Availability of treatments
a. disease lacking a treatment
b. treatment for resistant or non-responding patients
c. disease with a known treatment
3. Extent of the effect
a. clinical ‘hard’endpoint
b. partial benefit
c. minor or temporary benefit
The industry then negotiates a price with AIFA, which can
either accept, accept with restraint, or refuse to reimburse on
the NHS.
As a conditional approval, the medicine can be prescribed
within the NHS with fewer indications than those approved in
the EMA SmPC. When the advantage is minor or not so clear,
a ‘risk sharing’ or ‘payment by results or by performance’
method of pricing is adopted. This practice has permitted the
combining of a high need for effective drugs with high reimbursement costs, offering rapid access to some medicines whose
therapeutic and economic value is still uncertain. Figure 1
explains the most common features of the method.
The risk-sharing method requires an indicated use of the drug,
certified through the RFOM. In recent years, an increasing
number of Italian regions have set up reimbursement schemes
under devolved financial arrangements. These practices allow
clinical experience to be built while competent regional
authorities fund high-cost medicines to the local health
services. In the meantime, they provide access for patients to
highly innovative treatments.
Table 2: Comparison of the characteristics of the national
(AIFA-onco) and the Veneto region (SIRFAC)
registries
Item
National registry Veneto region registry
AIFA-onco
SIRFAC
Start
December 2005
Aims
Appropriateness – Appropriateness – funded
risk sharing
access to high-cost oncology
drugs (DGR 4051/2007)
Selection Innovative drugs
criteria
High-cost oncology drugs
(IV)
Focus
20 drugs (to
present day)
11 drugs in 156 protocols
Shared
drugs
Bevacizumab, bortezomib, cetuximab,
pemetrexed, rituximab
Patients
All treated in
Italy
Residents of the Veneto
region
Patient
outcome
Yes
Not yet
Report/
query
Standard reports
Not yet
Updating Monthly (AIFA
oncology board)
At the Venetian Oncology Institute (Instituto Oncologico
Veneto), the hospital pharmacists deal with different information archives. They have integrated administrative archives and
national/regional registers by record linkage and data mining to
obtain information on length of treatment and, where available,
outcome data.
Every patient is checked for length of treatment, and allocated
in tables of frequency distribution and survival curves. The poor
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
Annual (regional oncology
committee and regional
therapeutic committee)
Table 3: Comparison of oncology drugs recorded in the
national (AIFA-onco) and the Veneto region
(SIRFAC) registries
Item
Monitored
oncology
drugs
In January 2008, the Veneto region set up a web-based registry,
to regulate the use of 11 high-cost IV oncology medicines that
are specifically funded. This registry is stricter than AIFAonco and requires specific protocols in a complete medical
record. Tables 2 and 3 show the differences between the
two registries.
The registeries can follow a huge cohort of oncology patients
and enable inferences to be made of the effectiveness, toxicity
and real costs of the treatments.
January 2008
Accrual
closed
(only data
update)
National registry
AIFA-onco
bevacizumab, bortezomib,
cetuximab (colorectal
cancer), dasatinib,
erlotinib, everolimus,
gefitinib, ibritumomab,
lapatinib, lenalidomide,
nelarabine, nilotinib,
panitumumab,
pemetrexed, rituximab,
sorafenib, sunitinib (renal
cancer), temsirolimus,
thalidomide, trabectedine
carmustine wafer,
trastuzumab (adj),
oxaliplatin (adj),
aprepitant, fulvestrant,
temoporfin, palifermin
Veneto region
registry SIRFAC
alemtuzumab,
bevacizumab,
bortezomib,
cetuximab,
docetaxel,
irinotecan,
oxaliplatin,
paclitaxel,
pemetrexed,
rituximab,
trastuzumab
results obtained by some treatments (unpublished data and data
in press) confirm the need for the risk-sharing option of AIFA and
highlight the differences between real life treatment and clinical
trials, where efficacy is obtained from data on selected patients.
Author and References
Author and References can be found on page 29.
www.ejop.eu
25
Update
For personal use only. Not to be reproduced without permission of the publisher ([email protected]).
Cytotoxics in the pipeline: carrier-mediated
anticancer agents in development
Novel cancer pharmacotherapeutics are progressing speedily and are being implemented to solve several limitations of conventional chemotherapy. In this review, we will focus on the types and characteristics of carriermediated anticancer agents, how they are being used as drug delivery, and possible future advances.
Introduction
released drug) [9]. The released drug has also
In 2015, cancer chemotherapy will commembeen called the legacy drug, regular drug, or
orate its 70th anniversary since nitrogen muswarhead consisting of a drug that is both protard was introduced. Currently, nearly a huntein bound and unbound, see Figure 1.
dred drugs have been registered worldwide
for the treatment of cancer, but the rate of
The drug that remains encapsulated in or linked
cytotoxics development has been held back
to the carrier, e.g. nanoparticle, is an inactive
due to the increasing cost burden of conductprodrug, and must be released from the carrier
to be active.
ing clinical trials. Since a number of previously approved anticancer agents have gone
Suphat Subongkot
off-patent, the carrier-mediated cytotoxic
How carrier-mediated anticancer
PharmD, BCPS, BCOP
agents will likely be developed to improve
agents work
their efficacy and safety profiles for forthcoming applications.
Ideally, for anticancer agents to be effective in cancer treatment,
they should be able to reach the preferred tumour tissues through
Types and characteristics of carrier-mediated
the penetration of barriers in the human body with negligible loss
anticancer agents
of their quantity or activity in the blood circulation. Secondly,
The major types of carrier-mediated anticancer agents are nanoparafter reaching the tumour tissue, drugs should have the capabiliticles, nanosomes, and conjugated agents consisting of polymerty to selectively destroy tumour cells without affecting normal
linked and pegylated agents [1-4]. Nanoparticles are submicroncells via a controlled release system of the active drug.
sized particles (3–200 nm), or systems that can be prepared using a
range of substances including polymers (polymeric nanoparticles,
Conventional cytotoxic drugs are typically trapped in the cirmicelles, or dendrimers), lipids (liposomes), viruses (viral nanoparculation by the RES. In contrast, the carrier-mediated antiticles), and organometallic compounds [5]. The size of nanoparticancer agents meet the size and surface characteristic requirecles used in a drug delivery system should be bulky enough to prements described above for escaping RES capture and have the
vent their rapid leakage into blood capillaries but compact enough
ability to circulate for longer periods in the bloodstream with
to escape capture by macrophages located in the reticulo-endothea greater chance of getting to the desired tumour tissues [10].
lial system (RES), such as the liver and spleen [6-8].
These features are described as the enhanced permeability and
retention effect. This effect constitutes an important mechaThe nomenclature used to describe the pharmacokinetic disponism by which macromolecules, including carrier-mediated
sition of carrier-mediated drugs is encapsulated or conjugated,
anticancer agents with a molecular weight > 50 kDa and size
released, and sum total (encapsulated or conjugated drug plus
≤ 100 nm, can selectively build up in the tumour interstitial
tissue [10]. Consequently, the primary sites of accumulation
Figure 1: Nomenclature of carrier-mediated anticancer
are the targeted tumour leading to a better therapeutic index
agents
and with the potential to overcome resistance associated with
the regular anticancer agent.
How to improve carrier-mediated anticancer
agents functionality
Currently, pegylated STEALTH liposomal doxorubicin and
paclitaxel albumin-bound particles are the only two members
of this relatively new class of agents approved for the treatment of cancer in the US [11-12].
Paclitaxel albumin-bound system (Abraxane) uses a nanoparticulate shell constructed from albumin [12]. A major advantage of
nanoshells is that they can be targeted to specific cell populations
through conjugation with a monoclonal antibody. When the
28
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
www.ejop.eu
nanoshell reaches the target site, it is ruptured using a low intensity light source such as a laser, and the therapeutic contents are
released. This provides high target specificity with high potential
for treatment of cancer with the chemotherapy agent paclitaxel,
which normally has some possible life-threatening side effects
due to a castor oil based solvent, cremophor.
In addition to the above products, nonpegylated liposomal formulations of doxorubicin and daunorubicin are also approved
in Europe for the treatment of breast cancer and Kaposi’s
Sarcoma, respectively [13].
There are a number of nanosomal, nanoparticle, and conjugated anticancer agents currently in preclinical and clinical development. These include topoisomerase inhibitors (topotecan
and irinotecan derivatives), anthracyclines, antimetabolites
(pyrimidine, pyrimidine analogues, and antifolates), antimicrotubules (vinka alkaloids, and taxane derivatives), platinum
analogues (cisplatin and oxaliplatin analogues) and interferon
class agents.
Newer generations of carrier-mediated agents containing two
anticancer agents within a single nanosome or nanoparticle
and antibody-targeted nanosomes and nanoparticles that may
improve selective cytotoxicity are in evaluation. Future multifunctional nanoparticles will be designed to have the ability to
carry one or more therapeutic agents, or carry imaging signal
amplification media, by way of co-encapsulated contrast
agents. These nanoparticles will eventually be able to target
tumour cells (active targeting moiety), visualise their location
in the body (real-time in vivo imaging), destroying the cancer
cells with no side effects by saving ordinary cells (active targeting and controlled drug release system), and monitor the
treatment outcome in real time [14-15]. Nevertheless, future
studies are still required in order to evaluate the mechanism of
clearance of carrier-mediated agents and identify factors associated with the pharmacokinetic and pharmacodynamic variability of carrier agents in patients and specifically in tumours
for more predictable responses.
Author
Assistant Professor Suphat Subongkot, PharmD, BCPS, BCOP
Pharmacy Practice Division
Faculty of Pharmaceutical Sciences
Khon Kaen University
Muang District, Khon Kaen 40002, Thailand
References
1. Drummond DC, Meyer O, Hong K, et al. Optimizing liposomes for
delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev.
1999;51:691-743.
2. Papahadjopoulos D, Allen TM, Gabizon A, et al. Sterically stabilized
liposomes: Improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci USA. 1991;88:11460-4.
3. D’Emanuele A, Attwood D. Dendrimer-drug interactions. Adv Drug
Deliv Rev. 2005; 57:2147-62.
4. Hillery AM, Lloyd AW, Swarbrick J, editors. Drug Delivery and
Targeting for Pharmacists and Pharmaceutical Scientists. CRC Press;
2001. p. 1-445.
5. Cho K, Wang X, Nie S, Chen Z, Shin DM. Therapeutic Nanoparticles
for Drug Delivery in Cancer. Clin Cancer Res. 2008;14(5):1310.
6. Wisse E, Braet F, Luo D, et al. Structure and function of sinusoidal
lining cells in the liver. Toxicol Pathol. 1996;24:100-11.
7. Yuan F, Dellian M, Fukumura D, et al. Vascular permeability in a
human tumor xenograft: molecular size dependence and cutoff size.
Cancer Res. 1995;55:3752-6.
8. Moghimi SM, Szebeni J. Stealth liposomes and long circulating
nanoparticles: critical issues in pharmacokinetics, opsonization and
protein-binding properties. Prog Lipid Res. 2003;42:463-78.
9. Zamboni WC. Liposomal, nanoparticle, and conjugated formulations
of anticancer agents. Clin Cancer Res. 2005;11:8230-4.
10. Maeda H. The enhanced permeability and retention (EPR) effect in
tumor vasculature: the key role of tumor-selective macromolecular
drug targeting. Adv Enzyme Regul. 2001;41:189-207.
11. Allen TM, Stuart DD. Liposomal pharmacokinetics. Classical, sterically stabilized, cationic liposomes and immunoliposomes. In: Janoff
AS, editor. Liposomes: Rational Design. New York: Marcel Dekker,
Inc; 2005. p. 63-87.
12. ABI 007. Drugs R D. 2004;5:155-9.
13. Allen TM, Martin FJ. Advantages of liposomal delivery systems for
anthracyclines. Semin Oncol. 2004;31(Suppl 13):5-15.
14. Kukowska-Latallo JF, Candido KA, Cao Z, et al. Nanoparticle targeting of anticancer drug improves therapeutic response in animal
model of human epithelial cancer. Cancer Res. 2005;65:5317-24.
15. Kam NW, O’Connell M, Wisdom JA, Dai H. Carbon nanotubes as
multifunctional biological transporters and near-infrared agents for
selective cancer cell destruction. Proc Natl Acad Sci USA. 2005;
102:11600-5.
An Italian model to evaluate appropriateness and effectiveness of drugs
Author and References (please see article on pages 24–25)
Author
References
Angelo C Palozzo, PharmD
Director of Pharmacy Department
Venetian Oncology Institute
64 Via Gattamelata
IT-35128 Padova, Italy
1. DiMasi JA. Tufts CSDD quantifies savings
from boosting new drug R&D efficiency.
Tufts Center for the Study of Drug
Development Impact Report. 2002;4(5):1-4.
2. Strom BL. How the US drug regulation safety
system should be changed. JAMA.2006;
295(17):2072-5.
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
3. Rawlins MD, Culyer AJ. National Institute
for Clinical Excellence and its value judgments. BMJ. 2004;329:224-7.
4. Motola D, De Ponti F, Poluzzi E, Martini N,
Rossi P, Silvani MC, et al. An update on the
first decade of the European centralized procedure: how many innovative drugs? Br J
Clin Pharmacol. 2006;62(5):610-6.
www.ejop.eu
29
Update
For personal use only. Not to be reproduced without permission of the publisher ([email protected]).
Erythropoiesis-stimulating agents in the
treatment of chemotherapy-induced anaemia
Erythropoiesis-stimulating agent(ESA)-related safety concerns mean that clinicians must be vigilant when prescribing ESAs in cancer patients.
ESA risks and benefits:
evolving guidance
risk of venous thromboembolic events
(VTEs). This follows a meta-analysis published in 2008 that suggested that ESA use
in cancer patients was associated with an
increased VTE risk [RR = 1.57, CI =
1.31–1.81]. However, it should be noted
that the analysis did not investigate the correlation between VTE risk and higher Hb
target levels [5].
Anaemia is a common complication in oncology patients receiving myelosuppressive
chemotherapy. As chemotherapy-induced
anaemia (CIA) may affect patients symptomatically and prognostically, a number of
treatment options are available, including red
blood cell (RBC) transfusions and recombinant ESAs. ESAs work by increasing and
Phebe Si
Assistant Professor
maintaining haemoglobin (Hb) concentra- BScPharm (Hons) Alexandre Chan, PharmD The European Organization for Research
and Treatment of Cancer (EORTC), the
tions, improving quality of life, alleviating
American Society of Hematology (ASH)/American Society of
fatigue, and reducing the chronic need for RBC transfusions [1, 2].
Clinical Oncology (ASCO), and the National Comprehensive
Cancer Network (NCCN) have also recently updated their eviSince 2007, published studies showing poor disease control and
dence-based guidelines on CIA management [6-8]. Currently, the
reduced overall survival have prompted a number of revisions to
EORTC recommends that in symptomatic patients and selected
ESA product labels, see Table 1 [3]. Revisions have included the
asymptomatic patients, ESAs should be initiated at Hb concenaddition of a black box warning, and the implementation of a risk
trations of 9–11 g/dL [6].
evaluation and mitigation strategy (REMS). Under REMS,
patients are required to provide informed consent before receiving
The ASH/ASCO and NCCN guidelines do not recommend
an ESA, and enrol in the Assisting Providers and Cancer Patients
ESA use in any patient not undergoing chemotherapy [7, 8].
with Risk Information for Safe Use of ESA (APPRISE) Oncology
Program [4]. Furthermore, the FDA has limited ESA use to noncurable patients receiving chemotherapy for palliative intent and
NCCS ESA utilisation review
advocates using the lowest possible doses, to help decrease the
Our institution conducted a drug utilisation review of ESA
Table 1: Studies demonstrating adverse outcomes following ESA use
Study
Tumour type
n
Hb target
(g/dL)
Achieved median Adverse outcome in ESAHb (g/dL)
containing arm
Chemotherapy
BEST
2000-0161
Metastatic breast cancer
Lymphoid malignancy
939
344
12.9
11.0
Decreased 12-month survival
Decreased overall survival
PREPARE
Early breast cancer
733
12–14
13–15 (M)
13–14 (F)
12.5–13
13.2
GOG 0191
Cervical cancer
114
12–14
12.7
Decreased 3-year relapse-free
and overall survival
Decreased 3-year PFS and
overall survival and
locoregional control
Radiotherapy alone
ENHANCE
Head and neck cancer
351
> 15 (M)
> 14 (F)
14.4
DAHANCA
522
14–15.5
n/a
70
12–14
n/a
Decreased overall survival
989
12–13
10.6
Decreased overall survival
Head and neck cancer
No chemotherapy or radiotherapy
EPO-CAN-20
Non-small cell lung
cancer
2001-0103/
Non-myeloid
Amgen 103
malignancy
Decreased 5-year locoregional
PFS, locoregional progression
and overall survival
Decreased locoregional disease
control and overall survival
PFS: progression-free survival; ESA: erythropoiesis-stimulating agent.
30
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
www.ejop.eu
usage at the National Cancer Centre Singapore (NCCS). This
revealed that the recent safety advisories had triggered a
change in ESA prescribing, namely that clinicians had become
more cautious. We observed a lower mean Hb level (8.52 g/dL
vs 8.98 g/dL) for ESA initiation and a higher frequency of dose
adjustments for excessive responders. However, our findings
also showed that serum iron index monitoring and the provision of oral iron supplementation were still somewhat lacking
in our practice [9].
Conclusion
Although ESAs can effectively manage CIA, clinicians must
exercise caution when prescribing them. Clinicians must also
recognise their inherent risks, and follow the latest ESA-related guidance.
Authors
Phebe Si, BScPharm (Hons)
Pharmacist
1
Department of Pharmacy
National Cancer Centre Singapore
11 Hospital Drive
169610 Singapore
Assistant Professor Alexandre Chan1 , PharmD, MPH, BCPS, BCOP
Associate Consultant Clinical Pharmacist
Department of Pharmacy
National University of Singapore
18 Science Drive, Blk S4
117543 Singapore
References
1. Bohlius J, Wilson J, Seidenfeld J, et al. Erythropoietin or darbepoetin for
patients with cancer. Cochrane Database Syst Rev. 2006 Jul 19;3:
CD003407.
2. Littlewood TJ, Bajetta E, Nortier JW, et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebocontrolled trial. J Clin Oncol. 2001;19(11):2865-74.
3. Food and Drug Administration. FDA Receives New Data on Risks of
Anemia Drugs Consistent With Previous Data on Tumor Growth and
Death. Available from: www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ 2008/ucm116830.htm [Accessed 1 May 2011].
4. Food and Drug Administration. FDA Drug Safety Communication:
Erythropoiesis-Stimulating Agents (ESAs): Procrit, Epogen and
Aranesp [cited 2011 May 11]. Available from: www.fda.gov/Drugs/
DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvid
ers/ucm200297.htm
5. Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia.
JAMA. 2008;299(8):914-24.
6. Aapro MS, Link H. September 2007 update on EORTC guidelines and
anemia management with erythropoiesis-stimulating agents. Oncologist. 2008;13 Suppl 3:33-6.
7. Rizzo JD, Brouwers M, Hurley P, et al. American Society of
Hematology/American Society of Clinical Oncology clinical practice
guideline update on the use of epoetin and darbepoetin in adult
patients with cancer. Blood. 2010;116(20):4045-59.
8. National Comprehensive Cancer Network. Cancer- and Chemotherapy-Induced Anemia.V.2.2011.
9. Chan Q, Chan A. Impact of erythropoiesis-stimulating agent prescribing at an Asian cancer center, after release of safety advisories. J
Oncol Pharm Pract. Published online 2010 Jul 21. doi: 10.1177/
1078155210378058
For personal use only. Not to be reproduced without permission of the publisher ([email protected]).
NEWS FLASH
Germany tightens controls on pharmaceutical
prices
The German government is contemplating pharmaceutical
price control legislation as it battles soaring drug spending.
On the one hand Germany is keen to promote the use of
generic drugs and generic medicines have already achieved
high penetration—75% by volume in 2009. This highlights
opportunities for generic manufacturers in Europe’s largest,
albeit competitive, drug market.
On the other hand, the government is hoping to cut Euros 2
billion from the sum it currently spends on new drugs. If a
new law extends the current system of value-based pricing,
companies bringing new drugs to the market will have one
year to negotiate prices with health insurers. If no final price
agreement is made, the health ministry will set a maximum
price and the drug will face a cost–benefit analysis conduct-
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
ed by Germany’s Institute for Quality and Efficiency in
Healthcare (Institut für Qualität und Wirtschaftlichkeit im
Gesundheitswesen [IQWiG], Germany’s NICE). This type of
system will not automatically lead to lower prices, the
government and originator companies may agree a higher
price if it can be justified. But other governments are
watching with interest. If the new law is successful in lowering prices, it may lead to similar legislation in other
European countries.
The drug price reforms that have already been enacted will
also make a ‘severe’ dent in the sector’s revenues. The
mandatory discount that drug firms must offer to state health
insurers has risen from 6% to 16%, and a 3-year price freeze
will last until the end of 2013.
source: www.gabionline.net
www.ejop.eu
31
Conference Report
For personal use only. Not to be reproduced without permission of the publisher ([email protected]).
35th ESMO Congress report: recent advances
in cancer treatment
In this report, the major results of the clinical studies presented during the 35th ESMO Congress, which was
held on 8–12 October 2010 in Milan, Italy, are reviewed and analysed in terms of their implications for oncology
practice.
Introduction
A record number of attendees (16,000) made
the 35th ESMO Congress a resounding success, including over 13,000 oncologists and
other healthcare professionals involved in
cancer care, 380 media representatives and
close to 400 cancer patients who participated
in a dedicated seminar. All educational materials from the congress are available from
www.esmo.org/education/abstracts -and-virtual-meetings.html
advanced low- or intermediate-grade pancreatic
NETs showed a 65% reduction in the risk of
progression and an increase from 4.6–11.0
months in median PFS when everolimus was
combined with the best supportive care and
compared to placebo plus best supportive care.
This study was presented by Dr James Yao,
Anderson Cancer Center, Houston, USA [2, 3].
Svetlana Jezdic
MD
Randomised phase III practice-changing studies
Professor Johann de Bono, Institute for Cancer Research and
Royal Marsden Hospital, Surrey, UK, presented results of the
randomised double-blind placebo-controlled phase III study that
compared abiraterone acetate (potent and selective inhibitor of
CYP17α-hydroxylase) versus placebo in 1,195 patients with
castration-resistant metastatic prostate cancer. This is the first
clinical trial that prospectively studied hormonal therapy after
docetaxel treatment and the first clinical trial in prostate cancer
with prospective collection of circulating tumour cells. It is also
the first trial that prospectively used the Prostate Cancer Clinical
Trials Working Group criteria in the context of a randomised
phase III trial. Overall survival data shows clear advantages in
favour of abiraterone acetate compared to placebo (14.8 months
vs 10.9 months) and the drug also significantly improved time to
prostate-specific antigen (PSA) progression, radiographic progression-free survival (PFS), and PSA response rate. A decrease
in circulating tumour cells matches with the overall survival data
and side effects show almost no difference compared to placebo.
Further follow-up on survival data is awaited as well as a report
on the potential long-term side effects [1].
Novel targeted agents and randomised
trials
Dr David Spigel, Sarah Cannon Research
Institute, Nashville, USA, reported results of a study that
included 128 patients with advanced non-small cell lung carcinoma (NSCLC). Patients were randomly assigned to treatment
with either erlotinib plus placebo or erlotinib plus novel agent
MetMAb, a monoclonal antibody that binds specifically to the
MET receptor. This is the second trial in lung cancer where the
targeting of MET receptors in combination with erlotinib suggests a better outcome. Immunohistochemically, the MET-positive population derived a benefit in PFS, and also an almost
statistically relevant overall survival benefit. A note of caution
is that these phase II results need to be validated in a phase III
trial [4].
Dr Vincent Miller, Memorial Sloan-Kettering Cancer Center,
New York, USA, reported that no established therapy exists for
NSCLC patients who fail chemotherapy and erlotinib or gefitinib. Although the LUX-lung 1 study did not meet its primary
Treatment options for advanced neuroendocrine tumours
(NETs) are limited. In 429 patients with progressing well or
moderately differentiated advanced NETs and a history of carcinoid symptoms, everolimus, an oral inhibitor of mTOR pathway, was administered together with octreotide LAR, and
compared to placebo plus octreotide LAR. The study was presented by Dr Marianne Pavel, Charité University Hospital,
Berlin, Germany, who showed a 5.1-month clinically meaningful increase in median PFS for the everolimus combination
compared to placebo plus octreotide LAR. This should be considered for changing the current practice, as the alternative
treatment is octreotide or a very aggressive chemo-embolisation. Another clinically meaningful report on 410 patients with
32
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
www.ejop.eu
endpoint of extending overall survival, this does not diminish the
potential value of afatinib (BIBW 2992); this new, irreversible
inhibitor of EGFR/HER1 and HER2 induced objective regressions in heavily pre-treated NSCLC patients and led to a better
PFS with improvements in some of cancer-related symptoms [5].
Dr Georgina Long, Melanoma Institute Australia and Westmead
Hospital, Sydney, Australia, reported the results in a subgroup of
10 melanoma patients with previously untreated brain metastases
from the international phase I/II trial with the selective oral
inhibitor of V600 mutant BRAF kinase. The investigators
described activity of this targeted agent in brain metastasis. All
patients experienced control, and almost all
experienced reductions in the overall size of
their brain metastases. The overall reductions ranged from 20–100% of brain metastases that were > 3 mm before treatment.
The ability to inhibit oncogenic BRAF is the
most important development in the history
of melanoma drug treatment [6].
New formulations of old drugs
to innovate the therapeutic
armoury
Examples of successes in this area are
capecitabine and liposomal anthracyclines. Several new formulations of taxanes have been studied which aim to increase efficacy and/or
decrease toxicity. EndoTAG-1 is an innovative formulation
that tries to capitalise on the potential antiangiogenic proprieties of paclitaxel. In this new drug, paclitaxel is embedded in
cationic liposomes and targets activated endothelial cells of
tumour vessels. It is also innovative since it targets the environment and not the tumour cell itself. Results from the first
randomised phase II study of EndoTAG-1 targeting tumour
endothelial cells in advanced triple-negative breast cancer are
somewhat disappointing since EndoTAG-1 alone does not
seem to be a valid option, with PFS rate at week 16 inferior to
paclitaxel alone, albeit with overlapping confidence intervals.
Nevertheless, the apparent benefit of the combination arm
merits further evaluation in a subsequent study. This study was
presented by Dr Ahmed Awada of the Jules Bordet Institute,
Brussels, Belgium [7].
Supportive care
Trastuzumab has been shown to improve disease-free and overall
survival in patients with HER2-positive early-stage breast cancer.
Standard adjuvant treatment by trastuzumab requires 52 weekly
IV infusions over one year after chemotherapy and can result in
discomfort, inconvenience and a significant time commitment for
both healthcare providers and patients. Subcutaneous administration could significantly simplify treatment, shorten administration
and improve patient experience.
Recombinant human hyaluronidase has been developed and
approved to improve dispersion and absorption of co-adminis-
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
tered drugs. It has been combined with trastuzumab to allow
injection volumes ≥ 3 mL to be safely and comfortably administered SC. Dr Chris Wynne, Christchurch Clinical Studies
Trust, Christchurch, New Zealand, presented results of a phase
Ib study in which SC trastuzumab showed a tendency towards
even fewer administration-related reactions than IV trastuzumab; furthermore, it achieved a serum exposure comparable to
the approved IV formulation. The safety, tolerability and pharmacokinetic results of the study support the further testing of
SC trastuzumab [8].
Most cancer patients suffer from chronic pain. Controlled studies
with fentanyl pectin nasal spray demonstrate
a rapid onset of effect and greater clinically
meaningful pain relief compared to placebo
and oral morphine. A new technology allows
low-volume, fine-mist, and consistent particle-size delivery and therefore controlled
dosing. The study was presented by Dr Luis
Torres, Hospital Puerta del Mar, Cadiz,
Spain, who reported that fentanyl pectin
nasal spray can be easily titrated to an effective dose and could be used across a broad
range of opioid-tolerant cancer patients. This
is an interesting study but, as yet, it is too
early for a change of current practice. More
and more, nasal administration becomes a
convenient and efficient route of administration and has potential
for many other drugs [9].
In conclusion, the 35th ESMO Congress helped towards furthering our understanding of cancer biology, which should
drive the treatment of the right patient, at the right time, with
the right drug and dose.
The references referred to in the text are conference abstracts,
which are available from: www.esmo.org/education/abstractsand-virtual-meetings.html. The educational book containing
summaries of all educational sessions held during the 2010
Milan Congress can also be downloaded for free via this link.
Author
Svetlana Jezdic, MD
European Society for Medical Oncology
4 Via L Taddei
CH-6962 Viganello-Lugano, Switzerland
References
1. De Bono J, abstract LBA5.
2. Pavel M, abstract LBA8.
3. Yao J, abstract LBA9.
4. Spigel D, abstract LBA15.
5. Miller V, abstract LBA1.
6. Long G, abstract LBA27.
7. Awada A, abstract LBA12.
8. Wynne C, abstract 218PD.
9. Torres L, abstract 283PD.
www.ejop.eu
33
Conference Report
For personal use only. Not to be reproduced without permission of the publisher ([email protected]).
ASCO 2011: setting new standards in malignant
melanoma and myelofibrosis
The 2011 ASCO Annual Meeting, held on 3–7 June in Chicago, USA, included several landmark trials in malignant melanoma and myelofibrosis. This summary details some of the more interesting and relevant submissions.
Future cancer treatment strategies in
daily practice
Less is sometimes more
Oncologists regularly over-treat cancer patients.
However, the application of modern molecular
pathology techniques can help to reduce the use
of ineffective therapies, saving cancer patients
from undesired treatment effects, and saving the
healthcare system unnecessary expense. Two
important examples of this type of diagnostic
technique are OncotypeDx in breast cancer and
KRAS mutation testing in colorectal cancer.
ity in patients with advanced malignant melanoma
(BRAF V600-mutation-positive solid tumours).
These results are important because they suggest
promising synergistic anticancer activity for two
distinctly acting oral targeted therapies.
First-line ipilimumab immunotherapy plus
dacarbazine (DTIC) chemotherapy improves
overall survival in metastatic melanoma
A phase III trial by Wolchok J, et al., Memorial
Gertrud Lenzen
Sloan Kettering Cancer Center, New York, USA,
MD
has found that first-line treatment with a combination of ipilimumab (10 mg/kg) and standard DTIC chemotherapy
Preventing human cancer
(850 mg/m2) improves overall survival in patients with previously
Some human cancer entities have specific aetiologies that can be
untreated metastatic melanoma. This is the first study to show that
interrupted. For example, the introduction of human papillocombining DTIC chemotherapy with ipilimumab is safe and effecmavirus vaccines has led to a reduction in the incidence of cervitive in patients with advanced melanoma.
cal dysplasias, and similarly, Goss PE, et al., Massachusetts
General Hospital, Boston, USA, have demonstrated that exemesPalliative targeted therapy in JAK-positive primary myelofitane offers a new option in breast cancer prevention [1].
brosis, post-polycythemia vera-myelofibrosis or post-essential
thrombocythemia-myelofibrosis
The increasing importance of quality of life trials
A phase II trial by Harrison CN, et al., Guy’s and St Thomas’ NHS
Yoga improves sleep and reduces fatigue in post-chemotherapy
Foundation Trust, London, UK, has demonstrated that the JAK
patients. There are many specific quality of life improving techinhibitor, ruxolitinib, provides marked and sustained clinical beneniques, often ignored by oncologists, that can improve cancer
fit in spleen size and has an acceptable safety profile. These study
patients’ well-being. Such supporting therapies should be made
data may result in a new standard of care for a large number of
available as part of every primary standard treatment.
patients with myelofibrosis.
Trials that set new standards
Trials that change or confirm standard treatment
Vemurafenib (PLX4032) improves survival in advanced
malignant melanoma with V600E mutations in the BRAF gene
A phase III trial by Chapman P, et al., Memorial Sloan-Kettering
Cancer Center, New York, USA, has shown that vemurafenib,
which targets V600E mutations in the BRAF gene, improves overall survival in patients with advanced melanoma, when compared
to standard DTIC (1,000 mg/m2, IV, q3w). Vemurafenib is the first
drug to achieve improved overall survival in this patient group, and
the first drug to also improve progression-free survival.
Vemurafenib can now be regarded as standard treatment for
advanced melanoma in patients with this gene mutation.
Newly diagnosed diffuse large B-cell lymphoma: R-CHOP 14
is not superior to standard R-CHOP 21
Data from a randomised phase III trial by Cunningham D, et al.,
The Royal Marsden Hospital, London, UK, have indicated that
cyclophosphamide, doxorubicin, vincristine, prednisolone, and
rituximab administered every 14 days (R-CHOP14) does not
improve overall survival or progression-free survival in patients
with newly diagnosed diffuse large B-cell non-Hodgkin’s lymphoma, when compared with standard 21-day R-CHOP21 treatment. Patient status at 39 months, as measured by death, survival
without progression, survival with progression or relapse, death
with documented progression, and progression or relapse followed
by death, was virtually identical for the two cohorts.
Combining two distinctly acting oral targeted therapies shows
significant anti-tumour activity in patients with advanced
BRAF V600 mutation positive malignant melanoma
A phase I trial by Infante J, et al., Sarah Cannon Research Institute,
Nashville, USA, has shown that a combination of two oral targeted therapies—the oral MEK inhibitor GSK212 and the oral BRAF
inhibitor GSK436—is safe and has preliminary anti-tumour activ-
34
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
Standard first-line therapy of patients with chronic lymphocytic leukaemia (CLL)
Early-stage (Binet A and B, Rai 0-II) CLL patients who are asymptomatic do not usually require therapy. However, in patients with
advanced (Binet C, Rai III-IV) or active symptomatic disease,
www.ejop.eu
treatment should be initiated. For patients in good clinical condition, e.g. with a normal creatinine clearance and a low cumulative
illness rating score, fludarabine plus cyclophosphamide and rituximab is the standard first-line therapy [2]. Chlorambucil remains a
valid first-line treatment option for patients with relevant comorbidities. Patients with poor prognosis (del 17p and p53 mutation)
should be considered for cytoreductive therapy and allogeneic
stem cell transplantation following first remission.
Adjuvant treatment of operable gastrointestinal stromal
tumours with a high risk of recurrence
A phase III trial by Joensuu H, et al., Helsinki University Central
Hospital, Finland, showed that when compared with 1-year therapy, 3-year imatinib therapy (400 mg/day orally), administered following complete resection of a gastrointestinal stromal tumour
(GIST), improved overall survival and recurrence-free survival in
high-risk patients. This finding could lead to 3-year imatinib treatment becoming the new standard of adjuvant therapy in patients
with resected high-risk tumours.
sive disease could benefit from PCI, unless they have progressive
disease after primary therapy.
Dose-dense adjuvant temozolomid in newly diagnosed
glioblastoma
A phase III trial by Gilbert MR, et al., MD Anderson Cancer
Center, Houston, USA, has compared radiotherapy + concomitant
standard adjuvant temozolomid (TMZ) with radiotherapy + dosedense TMZ (ddTMZ), in 833 patients with newly diagnosed
glioblastoma (GBM). The standard TMZ regime comprised
150–200 mg/m2 for 5 days once a month and the dose-dense regimen was 75–100 mg/m2 for 21 days of each 4-week period for a
duration of 6–12 cycles. No differences in median overall survival
or median progression-free survival were observed between
groups, but increased overall survival was observed in patients
with O6-methylguanine-methyltransferase promoter (MGMT)
methylations. The authors concluded that MGMT methylation
status was an important determinant of treatment response in
patients with GBM.
Maintenance therapy for advanced non-squamous non-smallcell lung cancer (NSCLC)
A phase III trial by Paz-Ares L, et al., Seville University Hospital,
Spain, has shown that continuation maintenance therapy with
pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) after a 4-cycle
induction with pemetrexed (500 mg/m2) and cisplatin (75 mg/m2
on day 1 of a 21-day cycle) improves progression-free survival in
patients with non-squamous NSCLC. This is the first large trial to
demonstrate that longer-term maintenance therapy that
includes a drug that has been administered during induction
can increase progression-free survival in advanced NSCLC.
This study may have uncovered a new treatment option following first-line therapy.
Authors
Preoperative chemoradiotherapy and postoperative chemotherapy for locally advanced rectal cancer
A phase III trial by Roedel C, et al., University Hospital of
Frankfurt, Germany, has demonstrated that the inclusion of oxaliplatin to 5-FU-based chemoradiotherapy is well tolerated and
associated with increased pCR-rates, when compared with 5-FUchemoradiotherapy alone.
Klaus Meier, PharmD
Head Pharmacist
Zentralapotheke Heidekreis-Klinikum GmbH
30 Oeninger Weg
DE-29614 Soltau, Germany
Prophylactic cranial irradiation in small-cell lung cancer
Schild SE, et al., Mayo Clinic, Scottsdale, USA, have performed a
pooled analysis involving 739 patients with small-cell lung cancer
(stable disease or better following chemotherapy +/- thoracic
radiotherapy). The aim of the analysis was to determine whether
the subsequent administration of prophylactic cranial irradiation
(PCI) could improve survival. PCI was administered in 459
patients, at a total dose of either 30 Gy in 15 fractions or 25 Gy in
10 fractions. The remaining 280 patients received no cranial prophylaxis. The 1- and 3-year survival rates were 73% and 20% for
the PCI-receiving patients, and 52% and 6% for the non-PCI
patients (p < 0.0001). However, PCI did evoke an increase in
adverse events including alopecia, anaemia, and lethargy. The
investigators concluded that patients with either limited or exten-
European Journal of Oncology Pharmacy • Volume 5 • 2011/2
Professor Dr Wolfgang Wagner, MD, PhD
Professor of Radiotherapy
Department of Radiotherapy
Paracelsus Strahlenklinik Osnabrück
69 Am Nantruper Holz
DE-49076 Osnabruck, Germany
Gertrud Lenzen, MD (see photo)
Niels-Stensen-Kliniken
MVZ Onkologie
30 Bischofsstrasse
DE-49074 Osnabrück, Germany
Professor Dr Günther J Wiedemann, MD, PhD
Professor of Medicine
Department of Internal Medicine, Haematology, Oncology and
Gastroenterology
Oberschwabenklinik
12 Elisabethenstrasse
DE-88212 Ravensburg, Germany
References
1. Goss PE, Ingle JN, Alés-Martínez JE, Cheung AM, Chlebowski RT,
Wactawski-Wende J, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011 Jun 23;364(25):2381-91.
2. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et
al. Addition of rituximab to fludarabine and cyclophosphamide in patients
with chronic lymphocytic leukaemia: a randomised, open-label, phase 3
trial. Lancet. 2010 Oct 2;376(9747):1164-74.
www.ejop.eu
35
Conference Report
For personal use only. Not to be reproduced without permission of the publisher ([email protected]).
2011 EPAAC Open Forum
Professor Per Hartvig-Honoré, PharmD, PhD
The latest EPAAC Forum in Madrid, Spain, focused on cancer prevention and screening, and called for more
uniform standards of cancer care across Europe.
T
he European Partnership for Action Against
Cancer (EPAAC) was launched in 2009, following the publication of a European Commission
report titled Communication on Action Against
Cancer: European Partnership.
The aim of the Partnership initiative is to conjoin the efforts of
different stakeholders to prevent and control cancer. In its initial phase, until early 2014, the work of the Partnership will be
driven via a Joint Action (co-financed by the EU Health
Programme). The National Institute of Public Health in
Slovenia has assumed the role of leader of the EPAAC Joint
Action, which encompasses 38 European associated partners
and over 90 collaborating partners.
On 14–15 June 2011, the first of three EPAAC Open Forums was
held in Madrid, Spain. The Forum’s remit was to present the latest
EPAAC working initiatives, the first of which focuses on cancer
prevention. The highest risks for cancer, such as smoking, obesity,
low physical activity, lower alcohol consumption, avoiding sun
exposure, and avoiding cancerogenic substances, are well established. Nevertheless, ‘we do not do what we know we should do’,
i.e. although these risk factors are obvious, there is only a very
slow increase in adherence with regards to risk factor avoidance.
EPAAC has developed excellent educational campaigns for a variety of cancers, and each May, it runs a dedicated European Week
Against Cancer. This encompasses media advertisements, information leaflets, and campaign caps, all of which have helped to
spread the word about the dangers of cancer to the general public.
However, rather than resting on its laurels, additional campaign
events and educational literature are expected in future years.
Cancer care initiatives are currently fragmented across Europe.
Many countries have their own treatment standards, with
national practices often producing significantly different
results from larger international trials. Research also tends to
be fragmented. Research funding in the smaller countries is
often restricted to that country alone, meaning that some
research is duplicated, that the trials do not have sufficient
patient numbers, and that the quality of the trials is often lacking. On a pan-European level, there are a number of eminent
stakeholders such as patient organisations and industry representatives that would like to support and foster this research. The
coordination of this support is currently lacking however. There
are also important areas in cancer care that are often overlooked,
including psychosocial care, pain control, management of vomiting and fatigue, nutritional support, and rare-cancer care. These
important issues are also a focus for EPAAC.
The take-home message from the Open Forum was that despite us
knowing a great deal about cancer care, best practice is often not
delivered. Best practice implementation is often time-consuming, is
rarely adhered to, and not extensively practised. During a poster
presentation at the Forum, ESOP stated that it would very much like
to become an active partner in this fight against cancer, and that in
keeping with extensive and increasing evidence, any such initiatives required a multi-disciplinary professional approach.
Another EPAAC initiative focuses on cancer screening. EPAAC
has devised an initiative to develop specific screening tests, create
a process of qualification and validation, and satisfy uptake of current and future guidelines to facilitate wider use. Standard tests
have already been developed for breast, cervical, and colon cancers,
but the initiative is also now seeking to incorporate Hepatitis B
vaccination. There are various cancer registers in Europe, and the
type of information they contain often differs. This makes it difficult to make valid comparisons. There is therefore a clear need
both to better utilise existing registers, and compile new, more efficient and uniform registers which can increase our current knowledge. It is well known that cancer prevalence and disease outcomes vary widely across Europe, not least because of the diverse
management and governance infrastructures. New studies now
show that even in countries with restricted economies, the implementation of standards and good adherence can decrease mortality
dramatically. Moreover, these results are only marginally less successful than those seen in countries with healthy economies.
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European Journal of Oncology Pharmacy • Volume 5 • 2011/2
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